Tesi: "Pharmacokinetic interactions"

1

McArdle, Elizabeth Karen. "Pharmacokinetic interactions of constituents of cannabis extracts". Thesis, University of Aberdeen, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.415480.

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The use of a whole plant cannabis extract, containing D⁹-tetrahydrocannabinol (THC) and cannabidiol (CBD) as the principal constituents, showed statistically significant improvements in the management of multiple sclerosis. Inhibition studies (e.g. IC₅₀ and K_i determinations) using phenotyped human liver microsomes and cDNA expressed human P450s (Supersomesâ demonstrated that CBD competitively inhibits the principal P450s involved in the THC biotransformation, CYP2C9 (K_i = 0.5 mM), CYP2C19) (K_i = 0.4 mM) and CYP3A4 (K_i = 0.07 mM. CBD inhibition of CYP3A4 was mechanism-based, which suggests that a CBD metabolite (e.g. CBD-hydroxyquinone) is involved in CYP3A4 inhibition. CBD differentially induced rat P450s, whereas THC had no discernible effects on rat P450s. CBD significantly increased CYP1A2 protein at 150 mg kg^-1, but showed no change in mRNA expression. In addition, CYP1A-dependent activity was inhibited by < 80 % by CBD. These results suggest that CBD may bind tightly to and modify the CYP1A2 active site, thereby stabilising the protein but preventing substrate interaction. The significant increase in CYP2B1 mRNA implies that CBD transcriptionally regulates CYP2B, perhaps by activating CAR or through “cross-talk” by PXR. The 4-fold increase in CYP3A23 mRNA level suggests that CBD may be a weak ligand for PXR or that CBD is acting via CAR, which can also bind to response elements on the CYP3A23 gene. CBD is a potent inhibitor of P450-catalysed THC metabolism in vitro however pharmacokinetic modelling predicted that the therapeutic level of CBD (low nM range) after sublingual co-administration of THC and CBD (10 mg of each) was insufficient to inhibit THC metabolism of other human volunteers. This does not rule out the potential for CBD to inhibit the metabolism of other co-administered drugs in vivo. CBD may also induce the human orthologues of rat P450s, mainly CYP2B6 and CYP3A4, following extended periods of administration at high doses.

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2

Raaska, Kari. "Pharmacokinetic interactions of clozapine in hospitalized patients". Helsinki : University of Helsinki, 2003. http://ethesis.helsinki.fi/julkaisut/laa/kliin/vk/raaska/.

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3

Lundahl, Anna. "In vivo Pharmacokinetic Interactions of Finasteride and Identification of Novel Metabolites". Doctoral thesis, Uppsala universitet, Institutionen för farmaci, 2010. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-129362.

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The general aim of this thesis was to improve the understanding of the in vivo pharmacokinetics and, in particular, the metabolism of finasteride, a 5α-reductase inhibitor used in the treatment of enlarged prostate glands and male pattern baldness. CYP3A4 has been identified as the major enzyme involved in the sequential metabolism of finasteride to ω-OH finasteride (M1) and ω-COOH finasteride (M3). The consequences of induced and inhibited metabolism on the pharmacokinetics of finasteride and its metabolites were investigated in humans and pigs. Both studies included bile collection. The collected human and pig samples were used for the metabolite identification. As expected, induced metabolism led to reduced plasma exposure of finasteride and inhibited metabolism had the opposite effect. The interactions were investigated in detail and included examination of the biliary pharmacokinetics of finasteride and its metabolites. In pigs, the study included monitoring of the hepatic extraction over time, deconvolution and the development of a semi-physiological model for comparison of the effects on the gut wall and liver metabolism. For M3, the concentration ratios of bile to plasma and the renal clearance indicated that carrier-mediated processes are involved in the biliary and urinary excretion. This was not, however, the case for finasteride. The metabolite, M1, could not be quantified either in humans or pigs. Instead, two other OH metabolites, M1 isomers, were identified in humans. These metabolites were found to undergo glucuronide conjugation. In humans, one glucuronide was identified intact and in pigs, both glucuronides were identified intact in bile and in urine. In addition, a glucuronide of M3 was identified in human bile. In conclusion, advances have been made in the understanding of the pharmacokinetics of finasteride, in particular in relation to the metabolism. Hopefully, the findings of this comprehensive investigation can be applied to other drugs and novel chemical entities.

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4

Adedoyin, A. P. "Pharmacokinetic drug-drug interactions : inhibition and induction studies in the rat". Thesis, University of Manchester, 1986. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.376236.

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5

Elsherbiny, Doaa. "Pharmacokinetic drug-drug interactions in the management of malaria, HIV and tuberculosis". Doctoral thesis, Uppsala : Acta Universitatis Upsaliensis, 2008. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-8426.

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6

Yadav, Jaydeep. "EVALUATING PHARMACOKINETIC DRUG-DRUG INTERACTIONS DUE TO TIME DEPENDENT INHIBITION OF CYTOCHROME P450s". Diss., Temple University Libraries, 2018. http://cdm16002.contentdm.oclc.org/cdm/ref/collection/p245801coll10/id/524248.

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Pharmaceutical Sciences
Ph.D.
Time-dependent inactivation (TDI) of CYPs is a leading cause of clinical drug-drug interactions (DDIs). Current methods tend to over-predict DDIs. In this study, a numerical approach was used to model complex CYP3A TDI in human liver microsomes. Inhibitors evaluated include troleandomycin (TAO), erythromycin (ERY), verapamil (VER), Paroxetine (PAR), itraconazole (ITZ) and diltiazem (DTZ) along with primary metabolites N-demethyl erythromycin (NDE), norverapamil (NV), and N-desmethyl diltiazem (MA). Complexities incorporated in the models included multiple binding kinetics, quasi-irreversible inactivation, sequential metabolism, inhibitor depletion, and membrane partitioning. The different factors affecting TDI kinetics were evaluated such as lipid partitioning, inhibitor depletion, presence of transporters. The inactivation parameters obtained from numerical method were incorporated into static in-vitro – in-vivo correlation (IVIVC) models to predict clinical DDIs. For 123 clinically observed DDIs, using a hepatic CYP3A synthesis rate constant of 0.000146 min-1, the average fold difference between observed and predicted DDIs was 2.97 for the standard replot method and 1.66 for the numerical method. Similar results were obtained using a synthesis rate constant of 0.00032 min-1. These results suggest that numerical methods can successfully model complex in-vitro TDI kinetics and that the resulting DDI predictions are more accurate than those obtained with the standard replot approach. Chapter one presents the detailed introduction along with the hypothesis and significance of the project. Chapter 2 includes the development of the bioanalytical method for quantitation of various compounds which includes inactivators and their primary metabolites. Chapter 3 entails the discussion on in-vivo studies in rats involving TDI mediated DDI studies. Chapter 4 discusses the in-vitro studies and use of the numerical method for evaluation of TDI kinetics. Chapter 5 and chapter 6 provides discussion on the impact of inhibitor depletion and partitioning of TDI kinetics and how these two could lead to misinterpretation of TDI results. Chapter 6 also provides a discussion on how transporters could affect TDI results mainly from hepatocyte studies. Chapter 7 involves prediction of TDI mediated DDI using static modeling. Chapter 8 is a case study on bosentan involving induction mediated DDI.
Temple University--Theses

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7

Cherkaoui, Rbati Mohammed. "Mathematical and physical systems biology : application to pharmacokinetic drug-drug interactions and tumour growth". Thesis, University of Nottingham, 2016. http://eprints.nottingham.ac.uk/33719/.

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In this thesis, a multi-scale approach is provided to a pharmacokinetic and a pharmacodynamic problem. The first part of this research provides a realistic mathematical physiological model of the liver to predict drug drug interactions (DDIs). The model describes the geometry of a lobule (liver unit) and integrates the exchange processes, diffusion and active transport, between the hepatocytes and the blood and possible drug-drug interactions such as; reversible inhibition, mechanistic based inhibition (MBI) and enzyme induction. The liver model is subsequently integrated into a PBPK model with 7 compartments (artery blood, venous blood, gut, liver, kidney, lung, rest of the body). To assess the efficiency of the model to predict DDIs, 77 clinical DDI studies were compared to the model. These 77 clinical studies represent 5 victim drugs (midazolam, simvastatin, triazolam, cerivastatin and nifedipine) and 30 perpetrator drugs. The reversible inhibition, MBI and induction parameters for the majority of the perpetrators were estimated with in vitro experiments and adjusted for the human liver size. The PK parameters, such as clearance and absorption rate, and the physiological parameters were obtained from the literature. The DDIs were measured as the ratio of the AUC (Area Under the Curve of the blood concentration) or the ratio of the maximum concentration Cmax of the victim drug administered with and without the perpetrator drug. The predicted ratios were compared with the clinical observation by calculating the geometric fold error GMFE. The GMFE for AUCratio and Cmax,ratio were calculated to be 1.54 and 1.34, respectively. Moreover, the PBPK model excluding the gut compartment under-predicts both inhibition (lower AUCratio) and induction (higher AUCratio) which strongly suggests that the gut DDI component can not be neglected for accurate clinical prediction. However, the static combined model by Fahmi et al. [1, 2] without the gut component fortuitously predicts the clinical AUCratio better than inclusion with the gut component. To conclude, the model predicts DDIs relatively well as it is in the lower range of errors reported in the literature (1.47-2.00 [1, 2]). Moreover, the model is able to predict the pharmacokinetics of drugs and provides a dynamic description of the DDIs, such as the enzyme level and spatial distribution within a lobule. Furthermore, the perpetrator dose regimen can be changed or the error in the in vitro parameters can be integrated to observe their influences on the AUC ratio. The second part of this research explored the Warburg effect in a avascular tumour growth model incorporating a cell shedding term to account for tumour shrinkage. The tumour model was based on an extension of the Ward and King model [3], where two sub-populations; living cells and dead cells are considered. Three diffusion equations for glucose, lactate and the drug are considered and included into the model for growth rate, natural death rate and a death rate due to the drug. The simulation of the model without a drug shows similar behaviour to the original model by Ward and King despite the presence of the shedding term and predicts an extracellular pH of 6.8. However, when a drug treatment is added, the model is able to simulate the shrinkage of the tumour unlike the original model. Moreover, two scenarios with a basic, neutral and acidic drug were explored, assuming similar efficiency at physiological pH to assess the effect of changes in the extracellular pH. Acidic or weak base drugs seem to be more efficient in low pH environment as the fraction of neutral form is greater and therefore more drug is available to cross the cell membrane to reach its target.

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8

Naghmeh, Jabarizadekivi. "A Comparison of the Effect of Omeprazole and Rabeprazole on Clozapine Serum Concentrations". University of Sydney, 2008. http://hdl.handle.net/2123/2471.

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Master of Philosophy
Clozapine is a drug of choice for treatment of refractory schizophrenia, which is primarily metabolized by Cytochrome P450 1A2 (CYP1A2). Norclozapine is its main metabolite. There are reports of wide ranging gastrointestinal side effects associated with clozapine therapy, that result in concomitant administration of proton pump inhibitors to treat acid-related disorders. Omeprazole is an established CYP1A2 inducer, while an in vitro study has shown that rabeprazole is much less potent in this regard. There is no available information about the impact of rabeprazole on CYP1A2 activity in patients. Firstly, this information is essential when prescriptions are changed from omeprazole to rabeprazole to reduce medication costs. Therefore, the aim of this study was to compare the effects of rabeprazole and omeprazole on CYP1A2-mediated clearance (CL/F) of clozapine. Secondly, the effective dosage of clozapine varies widely among patients, making it necessary to individualize drug therapy with clozapine. The reason for dosage variation could be due to the influence of patient-related variables on clozapine plasma concentrations. Therefore, another aim of this study was to investigate the relationship between patient variables, such as age, gender, cigarette smoke, weight and body mass index and clozapine clearance (CL/F). A cross-over study design was used for this study. Twenty patients from Macquarie hospital who were receiving clozapine and rabeprazole (with no other interacting medications) were recruited in this study. Blood samples were taken at 30 min, 1 hr, 2 hr and 12 hr after a dose of clozapine. Rabeprazole was then replaced with omeprazole. After at least 1 month blood samples were again collected at the above corresponding intervals after clozapine. The plasma concentrations of clozapine and norclozapine were determined by high performance liquid chromatography. Abbottbase Pharmacokinetic Systems Software, which utilizes Bayesian forecasting, was used to estimate pharmacokinetic parameters of clozapine. The ratio of plasma norclozapine/clozapine concentrations at trough level was used to reflect CYP1A2 activity. No difference was observed in clozapine clearance (CL/F) and CYP1A2 activity during concurrent therapy with either rabeprazole or omeprazole. According to some studies CYP1A2 induction by omeprazole is dose dependent. Furthermore, since rabeprazole is a weak CYP1A2 inducer in vitro, we conclude that omeprazole and rabeprazole may not induce CYP1A2 activity when used at conventional therapeutic dosage (<40 mg/day). Hence, replacement of omeprazole with rabeprazole at conventional therapeutic dosages (20 or 40 mg daily) offers no advantages in the management of patients with schizophrenia on clozapine and no dose adjustment is required. Consistent with previous studies, clozapine concentrations were found to be significantly lower in cigarette smokers due to CYP1A2 induction. No relationship was found between age, gender, or weight and clozapine clearance (CL/F). However, body mass index showed a significant negative correlation with clozapine clearance (CL/F). Since weight gain and lipid accumulation are common side effects of clozapine they may be associated with a reduction of CYP1A2 activity and clozapine clearance (CL/F). Moreover, high lipoprotein levels may decrease the unbound fraction of clozapine and decrease the availability of clozapine for oxidation by cytochrome P450 enzymes. Therefore, it is concluded that omeprazole and rabeprazole may not induce CYP1A2 activity when used at conventional therapeutic dosage (<40mg/day). Hence, replacement of omeprazole with rabeprazole does not require the dose of clozapine to be adjusted. Moreover, the negative correlation between clozapine clearance (CL/F) and BMI is informative. Further studies are now required to clarify the relationship between BMI, lipoprotein levels and clozapine clearance in patients with schizophrenia.

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9

Naghmeh, Jabarizadekivi. "A Comparison of the Effect of Omeprazole and Rabeprazole on Clozapine Serum Concentrations". Thesis, The University of Sydney, 2007. http://hdl.handle.net/2123/2471.

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Abstract (sommario):

Clozapine is a drug of choice for treatment of refractory schizophrenia, which is primarily metabolized by Cytochrome P450 1A2 (CYP1A2). Norclozapine is its main metabolite. There are reports of wide ranging gastrointestinal side effects associated with clozapine therapy, that result in concomitant administration of proton pump inhibitors to treat acid-related disorders. Omeprazole is an established CYP1A2 inducer, while an in vitro study has shown that rabeprazole is much less potent in this regard. There is no available information about the impact of rabeprazole on CYP1A2 activity in patients. Firstly, this information is essential when prescriptions are changed from omeprazole to rabeprazole to reduce medication costs. Therefore, the aim of this study was to compare the effects of rabeprazole and omeprazole on CYP1A2-mediated clearance (CL/F) of clozapine. Secondly, the effective dosage of clozapine varies widely among patients, making it necessary to individualize drug therapy with clozapine. The reason for dosage variation could be due to the influence of patient-related variables on clozapine plasma concentrations. Therefore, another aim of this study was to investigate the relationship between patient variables, such as age, gender, cigarette smoke, weight and body mass index and clozapine clearance (CL/F). A cross-over study design was used for this study. Twenty patients from Macquarie hospital who were receiving clozapine and rabeprazole (with no other interacting medications) were recruited in this study. Blood samples were taken at 30 min, 1 hr, 2 hr and 12 hr after a dose of clozapine. Rabeprazole was then replaced with omeprazole. After at least 1 month blood samples were again collected at the above corresponding intervals after clozapine. The plasma concentrations of clozapine and norclozapine were determined by high performance liquid chromatography. Abbottbase Pharmacokinetic Systems Software, which utilizes Bayesian forecasting, was used to estimate pharmacokinetic parameters of clozapine. The ratio of plasma norclozapine/clozapine concentrations at trough level was used to reflect CYP1A2 activity. No difference was observed in clozapine clearance (CL/F) and CYP1A2 activity during concurrent therapy with either rabeprazole or omeprazole. According to some studies CYP1A2 induction by omeprazole is dose dependent. Furthermore, since rabeprazole is a weak CYP1A2 inducer in vitro, we conclude that omeprazole and rabeprazole may not induce CYP1A2 activity when used at conventional therapeutic dosage (<40 mg/day). Hence, replacement of omeprazole with rabeprazole at conventional therapeutic dosages (20 or 40 mg daily) offers no advantages in the management of patients with schizophrenia on clozapine and no dose adjustment is required. Consistent with previous studies, clozapine concentrations were found to be significantly lower in cigarette smokers due to CYP1A2 induction. No relationship was found between age, gender, or weight and clozapine clearance (CL/F). However, body mass index showed a significant negative correlation with clozapine clearance (CL/F). Since weight gain and lipid accumulation are common side effects of clozapine they may be associated with a reduction of CYP1A2 activity and clozapine clearance (CL/F). Moreover, high lipoprotein levels may decrease the unbound fraction of clozapine and decrease the availability of clozapine for oxidation by cytochrome P450 enzymes. Therefore, it is concluded that omeprazole and rabeprazole may not induce CYP1A2 activity when used at conventional therapeutic dosage (<40mg/day). Hence, replacement of omeprazole with rabeprazole does not require the dose of clozapine to be adjusted. Moreover, the negative correlation between clozapine clearance (CL/F) and BMI is informative. Further studies are now required to clarify the relationship between BMI, lipoprotein levels and clozapine clearance in patients with schizophrenia.

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10

Salem, Farzaneh. "Applications of physiologically based pharmacokinetic modelling to prediction of the likelihood of metabolic drug interactions in paediatric population and studying disparities in pharmacokinetics between children and adults". Thesis, University of Manchester, 2014. https://www.research.manchester.ac.uk/portal/en/theses/applications-of-physiologically-based-pharmacokinetic-modelling-to-prediction-of-the-likelihood-of-metabolic-drug-interactions-in-paediatric-population-and-studying-disparities-in-pharmacokinetics-between-children-and-adults(1fdefe9a-037a-4738-b92a-5904a60960db).html.

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Anticipation of drug-drug interactions (DDIs) in the paediatric population are merely based on data generated in adults. Hence decision on avoiding certain combinations or attempts to adjust and manage the doses under combination-therapy are mainly speculative from the knowledge of what occurs in adults. However, due to developmental changes in elimination pathways from birth to adolescents, the assumption of DDIs being similar in adults and children might not be correct. This thesis firstly identifies and quantitatively compares the reported DDIs in paediatric and adult populations through a systematic literature review of DDIs reported in paediatric subjects. The study highlights the clear paucity of the data in children younger than 2 years. Therefore, the logical approach to test this hypothesis has been through modelling and simulation and incorporation of the biological knowledge on ontogeny of various enzymes and other elimination routes. The magnitude of any metabolic DDI depends on fractional importance of inhibited pathway which may not necessarily be the same in young children when compared to adults. To show this disparity between rate of ontogeny for metabolic pathways, the ontogeny pattern of CYP enzymes and renal function were analysed systematically. Bootstrap methodology was used to account for variability, and to define the age range over which a statistical difference is likely between each pair of specific pathways. A number of DDIs were simulated for virtual compounds to highlight the possibility that the magnitude of DDI can be influenced by age. Depending on the extent of contribution of metabolic pathways, neonates could be more sensitive to DDI than adults in certain scenarios or vice versa. Thus, extrapolation from adult DDI data may not be applicable across paediatric age groups. The uncertainty around the ontogeny functions based on in vitro information led us to carry out comprehensive performance verification for in vivo data on probe substrates of CYP1A2, -2C9 and 3A4 and assess the predictions of clearance (CL) by monitoring AUC. Although the evaluation showed that in most cases predictions were within two fold of observed data in adult and paediatric studies, the outcome suggests that the current ontogeny profiles result in under-prediction of CL values compared to clinical studies in infants and children and there is a need for better ontogeny models. Therefore, we derived novel ontogeny functions for CYP1A2 and CYP3A based on caffeine-theophylline and midazolam in vivo data. Age related CL data for caffeine, theophylline and midazolam were reconstructed back to intrinsic CL values per milligram of microsomal protein and best fit ontogeny models for CYP1A2 and CYP3A were derived from these data. The function for CYP1A2 describes an increase in relative intrinsic metabolic CL from birth to 3 years followed by a decrease to adult values. The function for CYP3A4 describes a continuous rise in relative intrinsic metabolic CL, reaching the adult value at about 2 years of age. The new models were validated by showing improved predictions of the systemic CL of ropivacaine (major CYP1A2 substrate; minor CYP3A4 substrate) and alfentanil (major CYP3A4 substrate) compared to those using a previous ontogeny function based on in vitro data. When implementing enzyme ontogeny functions it is important to consider potential confounding factors related to disease, anaesthesia and surgery that may affect the prediction of net in vivo CL. Finally, we demonstrated the application of paediatric physiologically-based pharmacokinetic (p-PBPK) models for calculation of sample size in paediatric clinical pharmacokinetic (PK) studies in a methodology suggested by Wang et al., based on desired precision for a PK parameter of interest. We obtained estimates of variability for CL, volume of distribution and area under the plasma concentration-time curve for 5 different drugs from (i) adult and paediatric classic clinical PK studies, and (ii) p-PBPK combined with in vitro-in vivo extrapolation. The estimates were applied to the sample size calculation proposal methodology for non-compartmental analysis. There were clear and drug dependent differences in calculated sample size based on various estimates of variability and overall, there was no consistent discrepancy in the sample size calculated according to the source of variability used for sample size calculations. The results are discussed in terms of their potential impact on the clinical PK studies in children. In general, considering the sensitivity of paediatric clinical PK studies and paucity of data in this group of patients, the use of p-PBPK models may offer an interim solution to uncovering age bands with potential higher vulnerability to DDI. However, these models require further refinements and testing before widely used in clinical practice with confidence.

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11

Sall, Carolina. "In vitro-in vivo assessment of repaglinide metabolism and drug-drug interactions : towards a physiologically-based pharmacokinetic model". Thesis, University of Manchester, 2013. https://www.research.manchester.ac.uk/portal/en/theses/in-vitroin-vivo-assessment-of-repaglinide-metabolism-and-drugdrug-interactionstowards-a-physiologicallybased-pharmacokinetic-model(1b8eca49-bc68-484e-b921-2e324b4c5f00).html.

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Repaglinide is currently recommended as an in vivo CYP2C8 probe by the U.S. Food and Drug Administration (FDA), but the kinetic characterisation and enzymes involved in the elimination of this drug have not been fully delineated. In addition to its complex metabolism, polymorphism in the SLCO1B1 gene encoding for the hepatic uptake transporter organic anion transporting polypeptide 1B1 (OATP1B1) has been shown to impact repaglinide pharmacokinetics, further complicating the prediction of repaglinide clearance and drug-drug interactions (DDIs). The aim of this thesis was to firstly perform a systematic analysis of repaglinide metabolic pathways and thereby assess the contribution of specific enzymes to its clearance, and to secondly increase the understanding of repaglinide as a victim drug by implementing obtained in vitro metabolism data together with reported hepatic uptake parameters into a physiologically-based pharmacokinetic (PBPK) model. Furthermore, reported repaglinide DDIs, repaglinide AUC in different SLCO1B1 genotype groups and repaglinide P450 metabolite ratios were collated and critically analysed. The metabolism of repaglinide was characterised using a range of in vitro systems, namely pooled cryopreserved human hepatocytes, human liver microsomes (HLMs), human S9 fractions and recombinant P450 enzymes. The impact of in vitro systems on the analysis of repaglinide metabolic pathway was investigated and the importance of individual metabolic pathways studied. Definite differences in formation clearance ratios were found between CYP3A4 and CYP2C8 for the formation of M1 and M4 metabolites, resulting in a 60- and 0.05-fold M1:M4 ratio in recombinant CYP3A4 and CYP2C8, respectively. A major system difference was seen in clearances for the formation of M2, which is suggested to be a main metabolite of repaglinide in vivo. An approximately 7-fold higher unbound intrinsic clearance was observed in hepatocytes and S9 fractions in comparison to microsomes; the involvement of aldehyde dehydrogenase in M2 formation was shown for the first time. This systematic analysis revealed a comparable in vitro contribution from CYP2C8 and CYP3A4 to the metabolism of repaglinide.

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12

Samineni, Divya. "Pre-Clinical and Clinical Investigation of Pharmacokinetic and Pharmacodynamic Interactions between Darunavir, a Novel Protease Inhibitor and Rosuvastatin". University of Cincinnati / OhioLINK, 2011. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1314040722.

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13

Pinto, Marta Cruz Batista. "Interações medicamentosas relevantes no tratamento de doenças cardiovasculares". Master's thesis, [s.n.], 2014. http://hdl.handle.net/10284/4519.

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Abstract (sommario):

Projeto de Pós-Graduação/Dissertação apresentado à Universidade Fernando Pessoa como parte dos requisitos para obtenção do grau de Mestre em Ciências Farmacêuticas
Os doentes cardiovasculares constituem um dos principais grupos de risco no que respeita à ocorrência de interações medicamentosas, não só pela combinação de fármacos usada no tratamento destas doenças como pelo facto de muitos indivíduos sofrerem igualmente de outras patologias que requerem medicação. A interação medicamentosa consiste na alteração da atividade farmacológica de um fármaco provocada pela administração anterior ou concomitante de outro e traduz-se numa resposta farmacológica diferente da prevista quando o mesmo fármaco é administrado isoladamente. As interações medicamentosas são classificadas tendo em conta o mecanismo de ação envolvido (farmacocinéticas ou farmacodinâmicas) e as substâncias que nelas intervêm (fármacos, alimentos ou produtos naturais). Algumas da interações são benéficas, podendo resultar, por exemplo, no aumento da eficácia terapêutica. Contudo, na maior parte das vezes, as interações medicamentosas culminam num efeito indesejado, designado reação adversa, importante causa de morbilidade e mortalidade. O presente trabalho monográfico visa compilar todas as possíveis interações com fármacos usados no tratamento da hipertensão arterial e na prevenção e/ou tratamento do acidente vascular cerebral descritas na literatura científica. É igualmente objetivo do presente trabalho a discussão e compreensão dos mecanismos envolvidos nas referidas interações e as suas consequências para a saúde do indivíduo. Adicionalmente, pretende-se referir de que forma as interações medicamentosas podem ser evitadas, abordando os sistemas de farmacovigilância implementados assim como as bases de dados disponibilizadas aos profissionais de saúde. The cardiovascular patients are a major risk group with regard of drugs interaction. This is not only due to the combination of drugs used in treatment of these diseases but also ause many individuals also suffer from other disorders requiring medication. Drug interaction is the modification of the pharmacological activity of a drug caused by prior or concomitant administration of another drug and results into a different pharmacological response that the one expected if the same drug had been administered alone. Drugs interaction are classified in relation to the mechanism of action involved (pharmacokinetic or pharmacodynamic) and substances taking part (drugs, food or natural products). Some interactions are beneficial, for example, the increase therapeutic efficacy. However, in most cases, they will culminate in unexpected effects, designated adverse reactions, that will lead to morbidity and mortality. The aim of this monograph is to compile all possible interactions between drugs used in the treatment of hypertension and in the prevention or treatment of stroke, described in the scientific literature. Another objective is the discussion and understanding of the mechanisms involved in these interactions and their consequences to the health of the individual. Additionally, it is intended to approach how drug interactions can be avoided by the use of pharmacovigilance systems as well as the databases available to health professionals.

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14

Arora, Priyanka. "Pharmacokinetic- Pharmacodynamic Investigations of Letrozole, a Potential Novel Agent for the Treatment of High-Grade Gliomas". University of Cincinnati / OhioLINK, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1552398989110981.

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15

Wiebe, Sabrina [Verfasser], e Gerd [Akademischer Betreuer] Mikus. "Midazolam Microdosing and Population Pharmacokinetic Modelling to Assess CYP3A Drug-Drug Interactions in Early Clinical Development / Sabrina Wiebe ; Betreuer: Gerd Mikus". Heidelberg : Universitätsbibliothek Heidelberg, 2021. http://d-nb.info/1229941436/34.

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16

Wojtyniak, Jan-Georg [Verfasser]. "Model Informed Drug Development and Precision Dosing for Drug-Drug-Gene-Interactions : Application of Physiologically-Based Pharmacokinetic Modeling / Jan-Georg Wojtyniak". Saarbrücken : Saarländische Universitäts- und Landesbibliothek, 2021. http://d-nb.info/1237268737/34.

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17

Darwich, Adam Saed. "Physiologically-based pharmacokinetic modelling and simulation of oral drug bioavailability : focus on bariatric surgery patients and mechanism-based inhibition of gut wall metabolism". Thesis, University of Manchester, 2014. https://www.research.manchester.ac.uk/portal/en/theses/physiologicallybased-pharmacokinetic-modelling-and-simulation-of-oral-drug-bioavailability-focus-on-bariatric-surgery-patients-and-mechanismbased-inhibition-of-gut-wall-metabolism(182c1e87-670c-4430-82ba-b335f6c13887).html.

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Understanding the processes that govern pre-systemic drug absorption and elimination is of high importance in pharmaceutical research and development, and clinical pharmacotherapy, as the oral route remains the most frequently used route of drug administration. The emergence of systems pharmacology has enabled the utilisation of in silico physiologically-based pharmacokinetic (PBPK) modelling and simulation (M&S) coupled to in vitro-in vivo extrapolation in order to perform extrapolation and exploratory M&S in special populations and scenarios were concerns regarding alterations in oral drug exposure may arise, such as following gastrointestinal (GI) surgery or metabolic drug-drug interactions (DDIs).Due to the multi-factorial physiological implications of bariatric surgery, resulting in the partial resection of the GI tract, the inability to rationalise and predict trends in oral drug bioavailability (Foral) following surgery present considerable pharmacotherapeutical challenges. PBPK M&S is a highly implemented approach for the prediction of DDIs. Reoccurring issues have emerged with regards to predictions of the magnitude of mechanism-based inhibition (MBI) where overestimations of DDIs have repeatedly been reported for drugs exhibiting high intestinal extraction. The aim of this thesis was to explore the interplay between oral drug absorption and metabolism occurring in the GI tract through the exploration of the impact of bariatric surgery on oral drug exposure and by theoretically examining the nesting and hierarchy of enterocyte and enzyme turnover and its impact on MBIs in the small intestine. This would be carried out by utilising a systems pharmacology PBPK M&S approach under a general model development framework of identification and characterisation of critical intrinsic factors and parameters, model implementation and validation. Developed post bariatric surgery PBPK models allow a framework to theoretically explore physiological mechanisms associated with altered oral drug exposure pre to post surgery, which could be assigned to the interplay between dissolution, absorption and gut-wall metabolism, where dissolution and formulation properties emerged as the perhaps most important parameters in predicting the drug disposition following surgery. Model validation identified missing critical factors that are essential for additional model refinement. Developed post bariatric surgery PBPK models have the potential of aiding clinical pharmacotherapy and decision-making following surgery. A mechanistic PBPK model was developed to describe the hierarchical dependency of enzyme and enterocyte turnover in the small intestine. Predicted enzyme recovery using the nested enzyme-within-enterocyte turnover model may potentially account for reported overpredictions of mechanism-based inhibition. Developed models in this thesis showcase the advantage of PBPK M&S in the extrapolation of oral drug exposure to special population and the potential of a PBPK approach in understanding underlying the underlying mechanism governing Foral and additionally highlight the need for generation of interdisciplinary data to support model development.

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18

Chao, Zhang. "Population pharmacokinetic models describing drug-drug interactions and variability in HIV infected South Africans on protease inhibitor-based antiretroviral regimens with and without tuberculosis". Doctoral thesis, University of Cape Town, 2012. http://hdl.handle.net/11427/3372.

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Includes abstract.
Includes bibliographical references.
Lopinavir/ritonavir is an important component of the first-line and second-line antiretroviral treatment for young children and adults respectively in the current World Health Organization guidelines. Rifampicin, a key component of antituberculosis treatment, profoundly reduces lopinavir concentrations. Therefore, investigation of the optimal dosage regimens of lopinavir/ritonavir when co-administered with rifampicin-based antituberculosis treatment is needed urgently. Moreover, treatment adherence is associated with virological and clinical responses to antiretroviral treatment, and reduced adherence leads to the development of drug resistance. The projects in this thesis were designed to characterize the population pharmacokinetic parameters of lopinavir and ritonavir in HIV infected South Africans, to account for the drug-drug interactions between lopinavir, ritonavir and rifampicin, to investigate optimal dose regimens of lopinavir/ritonavir when administered with rifampicin, and to investigate new approach to evaluate adherence.

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19

Lê, Minh. "L'apport de l'évaluation pharmacocinétique dans le choix des antirétroviraux (nature et dose) chez la personne vivant avec le VIH". Thesis, Sorbonne Paris Cité, 2019. http://www.theses.fr/2019USPCC020.

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En dépit des récentes avancées thérapeutiques, l’infection par le VIH pour être contrôlée nécessite le maintien à vie d’un traitement antirétroviral (ARV). De ce fait, des stratégies d’allègements destinées à réduire la « charge chimique » sont proposées afin de maintenir l’efficacité antivirale tout en améliorant le profil de tolérance. Les compartiments profonds tels que le compartiment central ou le tractus génital se révèlent des sanctuaires de réplication virale et nécessitent pour son contrôle, une pénétration optimisée des ARV depuis la circulation générale. Nous avons d’abord évalué la pénétration de maraviroc, raltégravir et rilpivirine dans les sécrétions génitales (liquide séminal et fluide cervico-vaginal) dans le cadre de stratégies antirétrovirales conventionnelles. Nous avons montré une bonne pénétration séminale de maraviroc et raltégravir et plus faible de rilpivirine. Ensuite, nous avons évalué, d’une part, l’exposition plasmatique de darunavir/ritonavir lors de l’allègement de dose quotidienne administrée de darunavir (essai ANRS-165 DARULIGHT), puis d’autre part, la pénétration séminale de darunavir avant et après allègement. Nous avons également pu caractériser une interaction réciproque complexe d’ordre pharmacocinétique entre darunavir et ritonavir. En effet, aucune différence significative d’exposition plasmatique et séminale n’a pu être démontrée malgré la réduction de moitié de la dose de darunavir. Ces résultats mettent en avant l’absence de linéarité des expositions plasmatiques respectives de darunavir et ritonavir dans l’explication de l’interaction. Enfin, nous avons évalué la pénétration séminale d’étravirine, raltégravir et son métabolite inactif glucuroconjugué, à partir d’une stratégie de maintenance en terme d’allègement du nombre d’ARV (essai ANRS-163 ETRAL). Si aucune interaction médicamenteuse métabolique n’était à redouter entre étravirine et raltégravir, nous avons montré qu’une interaction via les transporteurs d’efflux pouvait modifier la pénétration séminale de raltégravir et de son métabolite glucuroconjugué. Au final, les résultats de l’ensemble de ces travaux ont permis de préciser l’influence de la liaison aux protéines plasmatiques et aux protéines séminales (moindre) dans la pénétration et l’accumulation des ARV dans le tractus génital mâle et l’implication potentielle des transporteurs d’efflux
Despite the recent advances in HIV therapy, antiretroviral (ARV) treatment remains for life in order to control the HIV infection. Thus, maintenance strategies, developed to decrease the chemical burden of ARV, are evaluated to enhance the long-term tolerance with a similar efficacy to standard triple therapy. Anatomical sanctuaries such as central nervous system or genital compartment are sites of HIV replication. The penetration of ARV, from the systemic compartment to the deep compartments, is essential to control the HIV infection in these sanctuaries. First, we assessed the penetration of maraviroc, raltegravir and rilpivirine in genital fluids (seminal and cervico-vaginal fluids) in standard triple therapy. We reported a good penetration of maraviroc and raltegravir and mild penetration of rilpivirine in both genital fluids. Then, in a second project, we evaluated the plasma exposure of darunavir/ritonavir in a reduced daily-dose of darunavir in the ANRS-165 DARULIGHT study and the seminal penetration at both dosing regimen. We reported a complex pharmacokinetic interaction between darunavir and ritonavir: no significant difference was observed in both plasma and seminal exposure of darunavir, despite the 50% decrease of darunavir daily-dose. These results highlight the absence of linearity of both darunavir and ritonavir plasma exposures in the explanation of the interaction mechanism. Finally, we assessed the plasma exposure and the seminal penetration of etravirine, raltegravir and its inactive glucuronide metabolite in the ANRS-163 ETRAL study. No metabolic interaction was expected between etravirine and raltegravir. Nevertheless, we reported a probable interaction through the efflux transporters which might impact the seminal penetration of raltegravir and its metabolite. To summarize, our results from the different projects allowed to precise the influence of blood and seminal (in a lesser extent) plasma proteins in the penetration or accumulation of ARV in the male genital tract and the probable role of efflux transporteurs. Our results from the different projects contribute to assess the seminal penetration of ARV in relation with the respective plasma protein binding but also the elimination half-life and the probable role of efflux transporters

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20

Penson, Richard Thomas. "The morphine glucuronides : pharmacokinetics, pharmacodynamics and interactions". Thesis, Queen Mary, University of London, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.406201.

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21

Liu, Zhongqiu. "Mechanism of pharmacokinetic interaction between paeoniflorin and sinomenine". HKBU Institutional Repository, 2006. http://repository.hkbu.edu.hk/etd_ra/720.

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22

Li, Mengyao. "USING SEMIPHYSIOLOGICALLY-BASED PHARMACOKINETIC (SEMI-PBPK) MODELING TO EXPLORE THE IMPACT OF DIFFERENCES BETWEEN THE INTRAVENOUS (IV) AND ORAL (PO) ROUTE OF ADMINISTRATION ON THE MAGNITUDE AND TIME COURSE OF CYP3A-MEDIATED METABOLIC DRUG-DRUG INTERACTIONS (DDI) USING MIDAZOLAM (MDZ) AS PROTOTYPICAL SUBSTRATE AND FLUCONAZOLE (FLZ) AND ERYTHROMYCIN (ERY) AS PROTOTYPICAL INHIBITORS". VCU Scholars Compass, 2016. http://scholarscompass.vcu.edu/etd/4402.

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The purpose of the project was to investigate the impact of IV and PO routes difference for MDZ, a prototypical CYP3A substrate, and two CYP3A inhibitors (CYP3AI) -FLZ and ERY-, on the magnitude and time course of their inhibitory metabolic DDI. Individual semi-PBPK models for MDZ, FLZ and ERY were developed and validated separately, using pharmacokinetic (PK) parameters from clinical/in-vitro studies and published physiological parameters. Subsequently, DDI sub-models between MDZ and CYP3AIs incorporated non-competitive and mechanism-based inhibition (MBI) for FLZ and ERY, respectively, on hepatic and gut wall (GW) CYP3A metabolism of MDZ, using available in-vitro/in-vivo information. Model-simulated MDZ PK profiles were compared with observed data from available clinical PK and DDI studies, by visual predictive check and exposure metrics comparison. DDI magnitude and time course for CYP3AI (IV vs. PO) followed by MDZ (IV vs. PO) at various time points were predicted by the validated semi-PBPK-DDI models. Two hypothetical CYP3A substrates and four CYP3AI (derived from MDZ, FLZ and ERY, with GW metabolism removed, hepatic metabolism reduced, or oral bioavailability (Foral) and/or elimination half-life (t1/2) modified) were also simulated to generalize conclusions. The final semi-PBPK-DDI models predict well the PK profiles for IV/PO MDZ in absence/presence of IV/PO CYP3AI, with deviations between model-predicted and observed exposure metrics within 30%. Prospective simulations demonstrate that: 1) CYP3A substrates, e.g., MDZ, are consistently more sensitive to metabolic inhibition after PO than after IV administration, due to pre-systemic hepatic and/or GW metabolism. For substrates without GW metabolism and limited hepatic metabolism, only a marginal route difference for substrate administration is observed. 2) For high-Foral CYP3AIs, e.g., FLZ, no inhibitor IV-PO route DDI differences are expected, unless they are given simultaneously with PO MDZ. 3) For low-Foral CYP3AIs, e.g., ERY, greater inhibition is expected after IV than after PO administration for IV MDZ, but is difficult to predict for PO MDZ. 4) In addition to Foral and plasma t1/2 of CYP3AIs, the DDI onset, peak and duration are determined by their oral absorption rate and by the resulting hepatic and/or GW concentration profiles relative to Ki for noncompetitive CYP3AIs, but by CYP3A kinetics (synthesis, degradation rate) for MBI CYP3AIs.

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23

Bouwer, Máralien. "The pharmacokinetic interaction between cyclosporine and methoxsalen / Máralien Bouwer". Thesis, North-West University, 2003. http://hdl.handle.net/10394/331.

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Cyclosporine forms the cornerstone of therapy to prevent rejection after organ transplantation. However, the clinical use of the drug is compromised by a narrow therapeutic window and a wide inter- and intra-individual variation in metabolism. Cyclosporine is metabolised by the CYP3A4 isoenzymes in both the liver and intestine, while it has been reported that the metabolism of the drug can be inhibited by certain furocoumarin derivatives in grapefruit juice. Methoxsalen (8-methoxypsoralen) is a furocoumarin and a potent inhibitor of the cytochrome P450 system in both the liver and intestine. The study was conducted to investigate the possibility whether methoxsalen may inhibit the metabolism of cyclosporine and thereby increase the bioavailability of the drug. The interaction is of clinical relevance since both drugs are used in the treatment of psoriases. The study, conducted in 12 healthy male volunteers, was a three-way comparative bioavailability study with a wash out period of one week between treatments. The patients received 40 mg methoxsalen, 200 mg cyclosporine or a combination of the two on three separate occasions. Blood samples of 10 ml were collected by venupuncture at the following times: 0, 0.5, 1, 1.5, 2, 2.5, 3.4, 5,6, 8, 12 and 24 hours after drug administration. Methoxsalen was analysed by a high pressure liquid chromatograph method (HPLC) with UV detection (LOQ = 10 ng/ml), while cyclosporine was analysed using a fluorescence polarisation immunoassay (FPIA) technique. There was a statistical significant difference in AUCo-00 and Cmax ' for cyclosporine when methoxsalen was added to the drug regimen. When the methoxsalen levels were compared with those in the presence of cyclosporine, the levels were lower, although the difference was not statistical significant. We conclude that methoxsalen increase the levels of cyclosporine by inhibiting the P450 system enzymes in the liver and intestine. However, the absorption of methoxsalen is highly variable in the same individual which needs to be considered before this interaction can be regarded as being of any clinical relevance.
Thesis (M.Sc.(Pharmacology))--North-West University, Potchefstroom Campus, 2004.

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24

Muggli, Franco. "Pharmacokinetic and pharmacodynamic interaction between furosemide and metolazone in man /". [S.l : s.n.], 1986. http://www.ub.unibe.ch/content/bibliotheken_sammlungen/sondersammlungen/dissen_bestellformular/index_ger.html.

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25

Abebe, Bayew Tsega [Verfasser], Werner [Akademischer Betreuer] Siegmund, Siegmund [Gutachter] Werner e Hartmut [Gutachter] Derendorf. "In Vitro to In Vivo Extrapolation of Pharmacokinetic Drug Interactions between Clarithromycin and Ranitidine with Trospium Chloride to Evaluate Probe Drug Characteristics for P-glycoprotein and Organic Cation Transporter Functions in Human / Bayew Tsega Abebe ; Gutachter: Siegmund Werner, Hartmut Derendorf ; Betreuer: Werner Siegmund". Greifswald : Universität Greifswald, 2020. http://d-nb.info/1203299958/34.

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26

Abebe, Bayew Tsega [Verfasser], Werner Akademischer Betreuer] Siegmund, Siegmund [Gutachter] Werner e Hartmut [Gutachter] [Derendorf. "In Vitro to In Vivo Extrapolation of Pharmacokinetic Drug Interactions between Clarithromycin and Ranitidine with Trospium Chloride to Evaluate Probe Drug Characteristics for P-glycoprotein and Organic Cation Transporter Functions in Human / Bayew Tsega Abebe ; Gutachter: Siegmund Werner, Hartmut Derendorf ; Betreuer: Werner Siegmund". Greifswald : Universität Greifswald, 2020. http://nbn-resolving.de/urn:nbn:de:gbv:9-opus-34845.

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27

Sjögren, Erik. "Hepatic Disposition of Drugs and the Utility of Mechanistic Modelling and Simulation". Doctoral thesis, Uppsala universitet, Institutionen för farmaci, 2010. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-132571.

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The elimination of drugs from the body is in many cases performed by the liver. Much could be gained if an accurate prediction of this process could be made early in the development of new drugs. However, for the elimination to occur, the drug molecule needs first to get inside the liver cell. Disposition is the expression used to encapsulate both elimination and distribution. This thesis presents novel approaches and models based on simple in vitro systems for the investigation of processes involved in the hepatic drug disposition. An approach to the estimation of enzyme kinetics based on substrate depletion data from cell fractions was thoroughly evaluated through experiments and simulations. The results that it provided were confirmed to be accurate and robust. In addition, a new experimental setup suitable for a screening environment, i.e., for a reduced number of samples, was generated through optimal experimental design. The optimization suggested that sampling at late time points over a wide range of concentration was the most advantageous. A model, based on data from primary hepatocytes in suspension, for the investigation of cellular disposition of metabolized drugs was developed. Information on the relative importance of metabolism and membrane protein related distribution was obtained by analysis of changes in the kinetics by specific inhibition of the various processes. The model was evaluated by comparing the results to those obtained from an in vivo study analyzed with an especially constructed mechanistic PBPK model. These investigations showed that the suggested model produced good predictions of the relative importance of metabolism and carrier mediated membrane transport for hepatic disposition. In conclusion, new approaches for the investigation of processes involved in hepatic disposition were developed. These methods were shown to be robust and increased the output of information from already commonly implemented in vitro systems.

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28

Parkin, Donald Pysden. "A critical appraisal of the clinical pharmacokinetics of isoniazid". Thesis, Link to the online version, 1996. http://hdl.handle.net/10019.1/1267.

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29

Jokinen, Mika. "Effects of drug interactions and liver disease on the pharmacokinetics of ropivacaine". Helsinki : University of Helsinki, 2003. http://ethesis.helsinki.fi/julkaisut/laa/kliin/vk/jokinen/.

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30

Kim, Shinja Rhea. "Pharmacokinectic and pharmacodynamic aspects of cocaine and its interaction with ethanol". Diss., The University of Arizona, 1997. http://hdl.handle.net/10150/289511.

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The main purpose of the research described in this dissertation was to evaluate various aspects of cocaine in pharmacokinetics and pharmacodynamics including: physiologically based-pharmacokinetics modeling; the influence of ethanol on cocaine disposition. Further, cocaine and cocaethylene (CE) were compared using pharmacokinetic-pharmacodynamic (PK-PD) models. Lastly, PK-PD models after cocaine and a combination of cocaine and ethanol dose were developed. Cocaine was administered by iv with or without ethanol in rats. CE was formed only in the group of rats given cocaine in the presence of ethanol. The extent of benzoylecgonine formation from cocaine significantly suppressed in the presence of ethanol. There were no statistical differences in cocaine disposition kinetics following iv cocaine dose in the presence or absence of ethanol. The PB-PK model was developed to describe cocaine disposition in the rat, dog, monkey and ultimately for scaling to humans using information developed in animals. The model gave a good prediction of tissue concentration-time profiles in animals. The prediction of the plasma concentration-time data in humans was poor when using the same tissue-to-blood-partition coefficients (R) obtained in rats. However, an excellent prediction was obtained after R was adjusted for differences in the apparent volume of distribution at steady state (rat vs. humans). The PK-PD model for cocaine or CE was developed by analyzing literature data. CE appears to be less potent in producing euphorigenic effects and equipotent to cocaine in producing physiological effects (e.g., cardiovascular function). The sigmoid Emax model was selected to describe the relationship between the physiological and euphorigenic effects produced by cocaine, ethanol and CE and their respective concentrations in the effect compartment. This model gave a good prediction for those effects. It appears that increased heart rate and "cocaine high" after a combination dose of cocaine and ethanol compared to cocaine alone was due to both the increase in cocaine concentration and the CE formed following ethanol exposure. Similarly, increased effect of "any high" or "good effect" after a combined dose appears to be due to cocaine (in the presence of ethanol), ethanol and CE formed in the presence of cocaine and ethanol.

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31

Robertson-Dallas, Shannon. "The pharmacokinetic interaction between zidovudine and trimethoprim-sulfamethoxazole in HIV-1 infected children". Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1998. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape11/PQDD_0027/MQ40854.pdf.

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32

Chen, Mingqing. "Interactions between multi-kinase inhibitors and solute carrier transporters". The Ohio State University, 2020. http://rave.ohiolink.edu/etdc/view?acc_num=osu1585741410361704.

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33

Astbury, Carol. "The pharmacokinetics, actions and interactions of suphasalazine in rheumatoid arthritis and inflammatory bowel disease". Thesis, University of Leeds, 1988. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.328902.

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34

Müller, Adrienne Carmel. "African traditional medicine-antiretroviral interactions : effects of Sutherlandia frutescens on the pharmacokinetics of Atazanavir". Thesis, Rhodes University, 2011. http://hdl.handle.net/10962/d1013373.

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In response to the urgent call for investigations into antiretroviral (ARV)-African traditional medicine (ATM) interactions, this research was undertaken to ascertain whether chronic administration of the ATM, Sutherlandia frutescens (SF) may alter the bioavailability of the protease inhibitor (PI), atazanavir (ATV), which may impact on the safety or efficacy of the ARV. Prior to investigating a potential interaction between ATV and SF in vitro and in vivo, a high performance liquid chromatography method with ultraviolet detection (HPLC-UV) was developed and validated for the bioanalysis of ATV in human plasma and liver microsomes. An improved and efficient analytical method with minimal use of solvents and short run time was achieved in comparison to methods published in the literature. In addition, the method was selective, linear, accurate and precise for quantitative analysis of ATV in these studies. Molecular docking studies were conducted to compare the binding modes and affinities of ATV and two major SF constituents, Sutherlandioside B and Sutherlandin C, with the efflux transporter, P-glycoprotein (P-gp) and the CYP450 isoenzyme, CYP3A4 to determine the potential for these phytochemicals to competitively inhibit the binding of ATV to these two proteins, which are mediators of absorption and metabolism. These studies revealed that modulation of P-gp transport of ATV by Sutherlandioside B and Sutherlandin C was not likely to occur via competitive inhibition. The results further indicated that weak competitive inhibition of CYP3A4 may possibly occur in the presence of either of these two SF constituents. The Caco-2 cell line was used as an in vitro model of human intestinal absorption. Accumulation studies in these cells were conducted to ascertain whether extracts and constituents of SF have the ability to alter the absorption of ATV. The results showed that the aqueous extract of SF significantly reduced ATV accumulation, suggesting decreased ATV absorption, whilst a triterpenoid glycoside fraction isolated from SF exhibited an opposing effect. Analogous responses were elicited by the aqueous extract and a triterpenoid glycoside fraction in similar accumulation studies in P-gp overexpressing Madin–Darby Canine Kidney Strain II cells (MDCKII-MDR1), which signified that the effects of this extract and component on ATV transport in the Caco-2 cells were P-gp-mediated. The quantitative analysis of ATV in human liver microsomes after co-incubation with extracts and components of SF was conducted to determine the effects of SF on the metabolism of ATV. The aqueous and methanolic extracts of SF inhibited ATV metabolism, whilst the triterpenoid glycoside fraction had a converse effect. Analogous effects by the extracts were demonstrated in experiments conducted in CYP3A4-transfected microsomes, suggesting that the inhibition of ATV metabolism in the liver microsomes by these SF extracts was CYP3A4-mediated. A combination of Sutherlandiosides C and D also inhibited CYP3A4-mediated ATV metabolism, which was in contrast to the response elicited by the triterpenoid fraction in the liver microsomes, where other unidentified compounds, shown to be present therein, may have contributed to the activation of ATV metabolism. The in vitro studies revealed the potential for SF to alter the bioavailability of ATV, therefore a clinical study in which the effect of a multiple dose regimen of SF on the pharmacokinetics (PK) of a single dose of ATV was conducted in healthy male volunteers. The statistical analysis showed that the 90 % confidence intervals around the geometric mean ratios (ATV + SF/ATV alone) for both Cmax and AUC0-24 hours, fell well below the lower limit of the "no-effect" boundary of 0.8 – 1.25, implying that the bioavailability of ATV was significantly reduced in this cohort of subjects. It may thus be concluded that if the reduction in bioavailability observed in this clinical study is found to be clinically relevant, co-administration of SF commercial dosage forms and ATV in HIV/AIDS patients may potentially result in subtherapeutic ATV levels, which may in turn contribute to ATV resistance and/or treatment failure. This research has therefore highlighted the potential risk for toxicity or lack of efficacy of ARV regimens which may result when ATMs and PIs are used concurrently and that patients and health care practitioners alike should be aware of these perils.

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35

Volz, Anke-Katrin [Verfasser]. "Modelling and simulation techniques to investigate pharmacokinetics, pharmacodynamics, and drug-drug interactions / Anke-Katrin Volz". Saarbrücken : Saarländische Universitäts- und Landesbibliothek, 2021. http://d-nb.info/1228333696/34.

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36

Kulmatycki, Kenneth M. "Disease-drug interactions, pharmacokinetics and pharmacodynamics of sotalol and lidocaine in the presence of inflammatory conditions". Thesis, National Library of Canada = Bibliothèque nationale du Canada, 2000. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape4/PQDD_0012/NQ59615.pdf.

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37

Yeh, Teng-Kuang. "Pharmacokinetics of anti-aids and anti-cancer drugs : implications on drug delivery and drug interaction /". The Ohio State University, 2002. http://rave.ohiolink.edu/etdc/view?acc_num=osu148654688938101.

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38

Jiang, Xuemin. "Effect of herbal medicines on the pharmacokinetics and pharmacodynamics of Warfarin in healthy subjects". University of Sydney. Pharmacy, 2004. http://hdl.handle.net/2123/651.

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Herbal medicines are widely used in our community. A survey of Australian consumers indicated that 60% had used complementary and/or alternative medicines in the past year with the majority not informing their doctor that they were using herbal medicines. Little is known about the potentially serious consequences of interactions between herbal and conventional medicines. Warfarin has an important role in treating people with heart disease, yet it has a narrow therapeutic range, is highly bound to plasma proteins, and is metabolised by cytochrome P450. This creates the potential for life-threatening interactions with other drugs and foods leading to excessive bleeding. Hence, warfarin is one of the most frequently investigated drugs for interaction studies. Early clinical reports suggest that there exists the potential for an interaction between warfarin and four herbal medicines: St John�s wort, ginseng, ginkgo and ginger. However, these herb-drug combinations have never been conclusively studied. The two clinical studies conducted as part of this research had an identical study design. Twenty-four healthy male subjects were recruited into the two separate studies. This was an open label, three-way crossover randomised study in twelve healthy male subjects, who received a single 25 mg dose of warfarin alone or after 14 days pre-treatment with St John�s wort, or 7 days pre-treatment with ginseng. Dosing with St John�s wort or ginseng was continued for 7 days after administration of the warfarin dose in study I or who received a single 25 mg dose of warfarin alone or after 7 days pre-treatment with recommended doses of ginkgo or ginger from single ingredient products of known quality. Dosing with ginkgo or ginger was continued for 7 days after administration of the warfarin dose in study II. Platelet aggregation, international normalised ratio (INR) of prothrombin time, warfarin enantiomer protein binding, warfarin enantiomer concentrations in plasma and S-7-hydroxywarfarin concentration in urine were measured in both studies. Statistical comparisons were made using ANOVA and 95% confidence interval (CI) for mean value and 90% CI for geometric mean ratio value are reported. n study I, the mean (95% CI) apparent clearance of S-warfarin after warfarin alone or with St John�s wort or ginseng were, respectively, 198 (174 � 223) ml/h, 269 (241 � 297) ml/h and 220 (201 � 238) ml/h. The respective apparent clearances of R-warfarin were 110 (94 � 126) ml/h, 142 (123 � 161) ml/h and 119 (106 � 131) ml/h. The mean ratio of apparent clearance for S-warfarin was 1.29 (1.16-1.46) and for R-warfarin was 1.23 (1.11-1.37) when St John�s wort was co-administered. The mean ratio of AUC0-168 of INR was 0.79 (0.70 - 0.95) when St John�s wort was co-administered. The urinary excretion ratio of S-7-hydroxywarfarin after administration of warfarin alone was 0.04 (0.03 � 0.06) mg/h and there was no significant difference following treatment with either St John�s wort 0.03 (0.02 � 0.04) mg/h or ginseng 0.03 (0.02 � 0.04) mg/h. The ratio of geometric means for S-7-hydroxywarfarin UER was 0.82 (0.61-1.12) for St John�s wort, and 0.68 (0.50-0.91) for ginseng. St John�s wort and ginseng did not affect the apparent volumes of distribution or protein binding of warfarin enantiomers. In study II, the mean (95% CI) apparent clearance of S-warfarin after warfarin alone, with ginkgo or ginger were 189 (167 � 210) ml/h, 200 (173 � 227) ml/h and 201 (171 � 231) ml/h, respectively. The respective apparent clearances of R-warfarin were 127 (106 � 149) ml/h, 126 (111 � 141) ml/h and 131 (106 � 156) ml/h. The mean ratio of apparent clearance for S-warfarin was 1.05 (0.98 -1.12) and for R-warfarin was 1.00 (0.93 -1.08) when co-administered with ginkgo. The mean ratio of AUC0-168 of INR was 0.93 (0.81 -1.05) when co-administered with ginkgo. The mean ratio of apparent clearance for S-warfarin was 1.05 (0.97 -1.13) and for R-warfarin was 1.02 (0.95 -1.10) when co-administered with ginger. The mean ratio of AUC0-168 of INR was 1.01 (0.93 -1.15) when co-administered with ginger. The urinary excretion ratio (UER) of S-7-hydroxywarfarin after administration of warfarin alone was 0.04 (0.03 � 0.05) mg/h and there was no significant difference following treatment with either ginkgo 0.04 (0.03 � 0.04) mg/h or ginger 0.03 (0.02 � 0.04) mg/h. The ratio of geometric means for S-7-hydroxywarfarin UER was 1.07 (0.69-1.67) for ginkgo, and 1.00 (0.64-1.56) for ginger. Ginkgo and ginger did not affect the apparent volumes of distribution or protein binding of either S-warfarin or R-warfarin. In conclusion, St John�s wort significantly induced the apparent clearance of both S-warfarin and R-warfarin, which in turn resulted in a significant reduction in the pharmacological effect of rac-warfarin. Ginseng, ginkgo and ginger at recommended doses affect neither clotting status, nor the pharmacokinetics or pharmacodynamics of either S-warfarin or R-warfarin in healthy subjects.

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Fasinu, Pius Sedowhe. "In vitro assessment of some traditional medications used in South Africa for pharmacokinetics drug interaction potential". Thesis, Stellenbosch : Stellenbosch University, 2013. http://hdl.handle.net/10019.1/85850.

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Thesis (PhD)--Stellenbosch University, 2013.
ENGLISH ABSTRACT: Introduction Earlier studies have shown the popularity of herbal products among people as traditional, complementary or alternative medication. One of the major clinical risks in the concomitant administration of herbal products and prescription medicine is pharmacokinetic herb-drug interaction (HDI). This is brought about by the ability of phytochemicals to inhibit or induce the activity of metabolic enzymes and transport proteins. The aim of this study was to investigate the potential of the crude extracts of popular medicinal herbs used in South Africa to inhibit major cytochrome P450 (CYP) enzymes and transport proteins through in vitro assessment. Methods Medicinal herbs were obtained from traditional medical practitioners and 15 were selected for this study. The selected herbal products were extracted and incubated with human liver microsomes to monitor the following reactions as markers for the metabolic activities of the respective CYP: phenacetin O-deethylation (CYP1A2), diclofenac 4‟-hydroxylation (CYP2C9), S-mephenytoin 4‟- hydroxylation (CYP2C19) and testosterone 6β-hydroxylation (CYP3A4). In addition, the influence of Lessertia frutescens (formerly Sutherlandia frutescens) and Hypoxis hemerocallidea was investigated on more isozymes: coumarin 7-hydroxylation (CYP2A6), bupropion hydroxylation (CYP2B6), paclitaxel 6α-hydroxylation (CYP2C8), bufuralol 1‟-hydroxylation (CYP2D6), chlorzoxazone 6- hydroxylation (CYP2E1) and midazolam 1‟-hydroxylation (CYP3A4/5). The generation of the CYPspecific substrates/metabolites were monitored and quantified with the aid of LC-MS/MS. The metabolic clearance of midazolam using cryopreserved hepatocytes was monitored in the presence of Lessertia frutescens and Hypoxis hemerocallidea. The potential of both to inhibit human ATP-binding cassette (ABC) transporter activity was assessed using recombinant MDCKII and LLC-PK1 cells overexpressing human breast cancer resistant protein (BCRP) and human P-glycoprotein (P-gp), respectively. Similarly, the potential for interactions with human organic anion transporting polypeptide (OATP1B1 and OATP1B3) was assessed using recombinant HEK293 cells over-expressing OATP1B1 and OATP1B3, respectively. Results Bowiea volubilis, Kedrostis Africana, Chenopodium album, Lessertia frutescens (methanolic extract), Hypoxis hemerocallidea, Spirostachys africana and Lessertia frutescens (aqueous extract), in ascending order of potency demonstrated strong inhibition of CYP1A2 activity (IC50 = 1-100 g/mL). Similarly, Emex australis, Alepidea amatymbica, Pachycarpus concolor, Lessertia frutescens, Capparis sepiaria, Kedrostis africana and Pentanisia prunelloides inhibited CYP2C9 with IC50 less than 100 g/mL. The following demonstrated strong inhibition of CYP2C19 with IC50 values less than 100 g/mL: Acacia karroo, Capparis sepiaria, Chenopodium album, Pachycarpus concolor, Ranunculus multifidus, Lessertia frutescens and Zantedeschia aethiopica. CYP3A4 was inhibited by Lessertia frutescens, Hypoxis hemerocallidea, Spirostachys Africana, Bowiea volubilis, Zantedeschia aethiopica, Chenopodium album, Kedrostis Africana, Acacia karroo, Emex australis, Pachycarpus concolor, Ranunculus multifidus, Capparis sepiaria and Pentanisia prunelloides. Time-dependent (irreversible) inhibition of CYP3A4/5 (KI = 296 μg/mL, kinact = 0.063 min-1) and delay in the production of midazolam metabolites in the human hepatocytes, leading to a 40% decreased midazolam upscaled in vivo clearance, was observed with Lessertia frutescens. Further, Lessertia frutescence inhibited the activity of P-gp (IC50 = 324.8 μg/mL), OATP1B1 (IC50 = 10.4 μg/mL) and OATP1B3 (IC50 = 6.6 μg/mL). Hypoxis hemerocallidea inhibited the activity of OATP1B1 (IC50 = 118.7 μg/mL) and OATP1B3 (IC50 = 290.1 μg/mL) with no potent inhibitory effects on P-gp. None of the two inhibited the activity of BCRP within the tested concentrations. Conclusion The result indicates the potential for HDI between the selected medicinal herbs and the substrates of the enzymes investigated in this study, if sufficient in vivo concentrations are achieved.
AFRIKAANSE OPSOMMING: Inleiding Vroeëre studies het aangedui dat die gebruik van plantaardige produkte as tradisionele, aanvullende en alternatiewe medikasie baie gewild is. Een van die grootste kliniese risiko‟s geassosieer met die gelyktydige gebruik van plantaardige produkte met voorskrifmedikasie is farmakokinetiese kruiegeneesmiddel interaksies (HDI). Hierdie interaksies word veroorsaak deur die vermoë van plantchemikalieë om die aktiwiteit van metaboliese ensieme en transportproteïene te inhibeer of te induseer. Die doel van hierdie studie is om ondersoek in te stel na die moontlikheid van onsuiwer ekstrakte van gewilde Suid-Afrikaanse medisinale kruie om die belangrikste sitochroom P450 (CYP)- ensieme en transportproteïene te inhibeer. Hierdie ondersoek sal plaasvind deur middel van in vitrostudies. Metodes Medisinale kruie is verkry vanaf tradisionele genesers, waaruit ŉ totaal van 15 kruie geselekteer is vir gebruik tydens hierdie studie. Die geselekteerde kruie is geëkstraheer en met menslike lewermikrosome geïnkubeer om die volgende reaksies as merkers vir die metaboliese aktiwiteit van die onderskeie CYP-ensieme te moniteer: fenasetien-O-deëtilasie (CYP1A2), diklofenak-4‟- hidroksilasie (CYP2C9), S-mefenitoïen-4‟-hidroksilasie (CYP2C19) en testosteroon-6β-hidroksilasie (CYP3A4). Afgesien van die voorafgaande, is ook die invloed van Lessertia frutescens en Hypoxis hemerocallidea op verskeie ander iso-ensieme ondersoek. Hierdie iso-ensieme is soos volg: koumarien-7-hidroksilasie (CYP2A6), bupropioonhidroksilasie (CYP2B6), paklitaksiel-6α-hidroksilasie (CYP2C8), bufuralol-1‟-hidroksilasie (CYP2D6), chloorsoksasoon-6-hidroksilasie (CYP2E1) en midasolaam-1‟- hidroksilasie (CYP3A4/5). Die produksie van CYP-spesifieke substrate/metaboliete is gemoniteer en deur middel van LC-MS/MS-analises gekwantifiseer. Die metaboliese opruiming van midasolaam deur middel van krio-gepreserveerde hepatosiete is gemoniteer in die teenwoordigheid van Lessertia frutescens en Hypoxis hemerocallidea. Die moontlikheid van beide om menslike ATPbindingskasset (ABC)-transporteerderaktiwiteit te inhibeer is bepaal deur die gebruik van rekombinante MDCKII- en LLC-PK1-selle wat onderskeidelik menslike borskanker-weerstandige proteïen (BCRP) en menslike P-glikoproteïen (P-gp) potensieel. Op ŉ soortgelyke wyse is die moontlikheid vir interaksies met menslike organiese anion-transportpolipeptiede (OATP1B1 en OATP1B3) bepaal deur rekombinante HEK293-selle te gebruik wat onderskeidelik OATP1B1 en OATP1B3 potensieel. Resultate Bowiea volubilis, Kedrostis Africana, Chenopodium album, Lessertia frutescens (metanol-ekstrak), Hypoxis hemerocallidea, Spirostachys africana en Lessertia frutescens (water-ekstrak), in toenemende potensie, het sterk inhibisie van CYP1A2-aktiwiteit (IC50 = 1-100 g/mL) getoon. In ooreenstemming met die voorafgaande resultate het Emex australis, Alepidea amatymbica, Pachycarpus concolor, Lessertia frutescens, Capparis sepiaria, Kedrostis africana en Pentanisia prunelloides CYP2C9 met IC50–waardes van minder as 100 g/mL geïnhibeer. Die volgende het sterk inhibisie van CYP2C19 met IC50-waardes van minder as 100 g/mL getoon: Acacia karroo, Capparis sepiaria, Chenopodium album, Pachycarpus concolor, Ranunculus multifidus, Lessertia frutescens en Zantedeschia aethiopica. CYP3A4 is deur Lessertia frutescens, Hypoxis hemerocallidea, Spirostachys Africana, Bowiea volubilis, Zantedeschia aethiopica, Chenopodium album, Kedrostis Africana, Acacia karroo, Emex australis, Pachycarpus concolor, Ranunculus multifidus, Capparis sepiaria en Pentanisia prunelloides geïnhibeer. Tydafhanklike (onomkeerbare) inhibisie van CYP3A4/5 (KI = 296 μg/mL, kinact = 0.063 min-1) en vertraging in die produksie van midasolaammetaboliete in menslike hepatosiete wat aanleiding gee tot ŉ 40% afname in midasolaam bepaal in vivo opruiming, is waargeneem met Lessertia frutescens. Lessertia frutescens het ook die aktiwiteit van P-gp (IC50 = 324.8 μg/mL), OATP1B1 (IC50 = 10.4 μg/mL) en OATP1B3 (IC50 = 6.6 μg/mL) geïnhibeer. Hypoxis hemerocallidea het die aktiwiteit van OATP1B1 (IC50 = 118.7 μg/mL) en OATP1B3 (IC50 = 290.1 μg/mL) geïnhibeer met geen betekenisvolle effekte op P-gp nie. Geen een van die twee het die aktiwiteit van BCRP geïnhibeer binne die konsentrasies waarin getoets is nie. Gevolgtrekking Die resultate van hierdie studie dui aan dat wanneer voldoende in vivo-konsentrasies bereik word, die moontlikheid vir kruie-geneesmiddel interaksies tussen die geselekteerde medisinale kruie en ensiemsubstrate ŉ werklikheid word.

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40

Awortwe, Charles. "Pharmacokinetic herb-drug interaction study of selected traditional medicines used as complementary and alternative medicine (CAM) for HIV/AIDS". Thesis, Stellenbosch : Stellenbosch University, 2015. http://hdl.handle.net/10019.1/96796.

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Thesis (DMed)--Stellenbosch University, 2015
ENGLISH ABSTRACT: Introduction The increasing intake of traditional medicines among HIV/AIDS patients in sub-Saharan Africa needs urgent consideration by clinicians and other healthcare providers since the safety of such medications are unknown. The pharmacokinetic parameters - Absorption, Distribution, Metabolism and Elimination (ADME) play important role in the safety evaluation of drugs, thus implicating drug metabolizing enzymes and transporters as critical indicators for herb-drug interactions. The objective of this study was to evaluate the risk potential of seven herbal medicines commonly consumed by HIV/AIDS patients for drug interactions applying in vitro models. In this study, inhibition and induction effects of the herbal medicines on cytochrome P450s (CYPs) 1A2, 2C9, 2C19, 2D6 and 3A4 as well as P-glycoprotein (P-gp) were investigated. Methods Herbal medicines – Lessertia frutescens, Hypoxis hemerocallidea, Kalanchoe integra and Taraxacum officinale were sourced from Medico Herbs, South Africa were identified by experts from Compton Herbarium, South African National Biodiversity Institute, Cape Town. Moringa oleifera, Echinacea purpurea and Kalanchoe crenata were obtained from the repository of the National Centre for Natural Product Research (NCNPR), University of Mississippi, USA. Reversible inhibitory effect of aqueous and methanol herbal extracts were evaluated in recombinant CYPs applying the fluorescent metabolites at specified excitation/emission wavelengths; CYP1A2 (3-cyano-7-hydroxycoumarin (CHC); 405/460 nm), CYP2C9, CYP2C19 and CYP3A4 (7-hydroxy-4-(trifluoromethyl)-coumarin (HFC); 405/535 nm) and CYP2D6 (7-hydroxy-4-(aminomethyl)-coumarin (HAMC); 390/460 nm). Comparative studies in human liver microsomes (HLM) and recombinant CYPs were conducted to investigate the inhibitory effect of methanol herbal extracts and fractions on 6β testosterone hydroxylation activity. Time dependent inhibitory (TDI) effect of the herbal extracts were evaluated applying the IC50 shift fold, normalized ratio and the NADPH-, time- and concentration-dependent approaches. Influence of herbal extracts on metabolic clearance of testosterone was assessed in both HLM and human hepatocytes. The effects of each herbal extract on expression of CYP1A2, CYP3A4 and MDR1 genes were evaluated in activated human pregnane X receptor (PXR) co-transfected HepG2 cells. Finally, the inhibitory effect of herbal extracts on P-gp was assessed using the calcein-acetoxymethyl ester (calcein-AM) uptake and the digoxin radiolabelled substrates in MDCKII-MDRI cells. Results The aqueous extracts of Moringa oleifera, Kalanchoe integra, Kalanchoe crenata, Echinacea purpurea and Lessertia frutescens demonstrated high risk of in vivo inhibition on CYPs 3A4 and 1A2 with Cmax/Ki >1.0. Methanol extracts of these herbal medicines also indicated potential risk of reversible drug interaction. The methanol extracts of M. oleifera, K. crenata and L. frutescens showed strong TDI effect on CYP3A4 with IC50 shift fold >1.5 and normalised ratio <0.7. Moringa oleifera intermediately reduced intrinsic clearance of testosterone in human hepatocytes (2 ≤ AUC ratio ≤ 5) when scaled up to humans. Methanol extracts of Echinacea purpurea up-regulated the expression of CYP1A2, CYP3A4 and MDR1 genes in activated PXR. Kalanchoe crenata and Echinacea purpurea indicated strong inhibition on P-gp by reducing transport of digoxin across hMDR1-MDCKII cell monolayer from basolateral to apical with IC50 values of 18.24 ± 2.52 μg/mL and 24.47 ± 4.97 μg/mL, respectively. Conclusion The herbal medicines especially M. oleifera, K. integra and E. purpurea have the potential to cause herb-drug interaction in vivo if sufficient hepatic concentration is achieved in humans.
AFRIKAANSE OPSOMMING: Inleiding Die verhoogde inname van tradisionele medisynes onder MIV/VIGS-pasiënte in sub-Sahara-Afrika verg dringend oorweging deur klinici en ander gesondheidsorgverskaffers, aangesien die veiligheid van sodanige medikasies onbekend is. Die farmakokinetiese parameters – Absorpsie, Distribusie, Metabolisme en Eliminasie (ADME) – speel ’n belangrike rol by die veiligheidsevaluering van geneesmiddels, en impliseer gevolglik geneesmiddel-metaboliserende ensieme en vervoerders as kritiese indikators vir krui-geneesmiddel-interaksies (HDI). Die oogmerk van hierdie studie is om die risikopotensiaal van sewe kruiemedisynes wat algemeen deur MIV/VIGS-pasiënte geneem word, vir geneesmiddel-interaksies te evalueer deur in vitro-modelle te gebruik. In hierdie studie is die inhiberings- en induseringsuitwerkings van die kruiemedisynes op sitochroom P450’s (verkort na CYP’s) 1A2, 2C9, 2C19, 2D6 en 3A4, sowel as P-glikoproteïen (P-gp), ondersoek. Metodes Kruiemedisynes – Lessertia frutescens, Hypoxis hemerocallidea, Kalanchoe integra en Taraxacum officinale – is van Medico Herbs, Suid-Afrika, bekom en deur kundiges van die Compton-herbarium, by die Suid-Afrikaanse Nasionale Biodiversiteitsinstituut, Kaapstad, geïdentifiseer. Moringa oleifera, Echinacea purpurea en Kalanchoe crenata is van die bewaarplek van die Nasionale Sentrum vir Natuurlike Produknavorsing (NCNPR) aan die Universiteit van Mississippi in die VSA verkry. Die omkeerbare inhiberende uitwerking van kruie-ekstrakte in water en metanol is in rekombinante CYP’s geëvalueer deur die gebruik van die fluoresserende metaboliete op gespesifiseerde opwekkings-/emissiegolflengtes; CYP1A2 (3-siaan-7-hidroksikumarien (CHC); 405/460 nm), CYP2C9, CYP2C19 en CYP3A4 (7-hidroksi-4-(trifluoormetiel)-kumarien (HFC); 405/535 nm) en CYP2D6 (7-hidroksi-4-(aminometiel)-kumarien (HAMC); 390/460 nm). Vergelykende studies van menslikelewermikrosome (HLM) en rekombinante CYP’s is uitgevoer om die inhiberende uitwerking van metanolkruie-ekstrakte en -fraksies op 6β-testosteroonhidroksileringsaktiwiteit te ondersoek. Die tydafhanklike inhiberende uitwerking (TDI) van die kruie-ekstrakte is geëvalueer deur gebruikmaking van die IC50-verskuiwingsvou-, die genormaliseerdeverhoudings- en die NADPH-, tyd- en konsentrasieafhanklike benaderings. Die invloed van kruie-ekstrakte op metaboliese testosteroonverheldering is in beide HLM en menslike hepatosiete geëvalueer. Die uitwerkings van elke kruie-ekstrak op die uitdrukking van CYP1A2-, CYP3A4- en MDR1-gene is in geaktiveerde menslike pregnaan-X-reseptor(PXR)-, ko-getransfekteerde HepG2-selle geëvalueer. Laastens is die inhiberende uitwerking van kruie-ekstrakte op P-gp geëvalueer, met gebruikmaking van die kalsien-asetoksimetiel-ester (kalsien-AM)-opname en die digoksien- radiogemerkte substrate in MDCKII-MDRI-selle. Resultate Die ekstrakte in water van M. oleifera, K. integra, K. crenata, E. purpurea en L. frutescens het ’n hoë risiko van in vivo-inhibering op CYP’s 3A4 en 1A2 met Cmaks/Ki >1.0 getoon. Ekstrakte van hierdie kruiemedisynes in metanol het verder potensiële risiko van omkeerbare geneesmiddelinteraksie getoon. Die ekstrakte van M. oleifera, K. crenata en L. frutescens in metanol het sterk TDI-uitwerking op CYP3A4 met IC50-verskuiwingsvou >1.5 en genormaliseerde verhouding <0.7 getoon. M. oleifera het intermediêre vermindering van intrinsieke testosteroonverheldering in menslike hepatosiete (2 ≤ AUC verhouding ≤ 5) tot gevolg wanneer die skaal na mense verhoog word. Ekstrakte van E. purpurea in metanol het die uitdrukking van CYP1A2-, CYP3A4- en MDR1-gene in geaktiveerde PXR opgereguleer. K. crenata en E. purpurea het sterk inhibering van P-gp getoon deur die vervoer van digoksien deur die hMDR1-MDCKII-selmonolaag van basolateraal tot apikaal met IC50-waardes van onderskeidelik 18.24 ± 2.52 μg/mL en 24.47 ± 4.97 μg/mL te verminder. Gevolgtrekking Kruiemedisynes, veral M. oleifera, K. integra en E. purpurea, het die potensiaal om HDI in vivo te veroorsaak indien voldoende hepatiese konsentrasie by mense bereik word.

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Chen, Chunli. "Pharmacokinetic-Pharmacodynamic Evaluations and Experimental Design Recommendations for Preclinical Studies of Anti-tuberculosis Drugs". Doctoral thesis, Uppsala universitet, Institutionen för farmaceutisk biovetenskap, 2017. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-318845.

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Tuberculosis is an ancient infectious disease and a leading cause of death globally. Preclinical research is important for defining drugs and regimens which should be carried forward to human studies. This thesis aims to characterize the population pharmacokinetics and exposure-response relationships of anti-tubercular drugs alone and in combinations, and to suggest experimental designs for preclinical settings. The population pharmacokinetics of rifampicin, isoniazid, ethambutol and pyrazinamide were described for the first time in two mouse models. This allowed for linking the population pharmacokinetic model to the Multistate Tuberculosis Pharmacometric (MTP) model for biomarker response, which was used to characterize exposure-response relationships in monotherapy. Pharmacodynamic interactions in combination therapies were quantitatively described by linking the MTP model to the General Pharmacodynamic Interaction (GPDI) model, which provided estimates of single drug effects together with a quantitative model-based evaluation framework for evaluation of pharmacodynamic interactions among drugs in combinations. Synergism (more than expected additivity) was characterized between rifampicin and ethambutol, while antagonism (less than expected additivity) was characterized between rifampicin and isoniazid in combination therapies. The new single-dose pharmacokinetic design with enrichened individual sampling was more informative than the original design, in which only one sample was taken from each mouse in the pharmacokinetic studies. The new oral zipper design allows for informative pharmacokinetic sampling in a multiple-dose administration scenario for characterizing pharmacokinetic-pharmacodynamic relationships, with similar or lower bias and imprecision in parameter estimates and with a decreased total number of animals required by up to 7-fold compared to the original design. The optimized design for assessing pharmacodynamic interactions in the combination therapies, which was based on EC20, EC50 and EC80 of the single drug, provided lower bias and imprecision than a conventional reduced four-by-four microdilution checkerboard design at the same total number of samples required, which followed the 3Rs of animal welfare. In summary, in this thesis the population pharmacokinetic-pharmacodynamic models of first-line drugs in mice were characterized through linking each population pharmacokinetic model to the MTP model. Pharmacodynamic interactions were quantitatively illustrated by the MTP-GPDI model. Lastly, experimental designs were optimized and recommended to both pharmacokinetic and pharmacodynamic studies for preclinical settings.

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Mogatle, Seloi. "African traditional medicines-antiretroviral drug interactions: the effect of African potato (Hypoxis hemerocallidea) on the pharmacokinetics of efavirenz in humans". Thesis, Rhodes University, 2009. http://hdl.handle.net/10962/d1003251.

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African Potato (Hypoxis hemerocallidea), (AP) is an African traditional medicine (TM) that is commonly used for various nutritional/medicinal purposes and also by people infected with the human immuno deficiency virus HIV and AIDS patients as an immune booster. The use of AP has also been recommended by the former Minister of Health of South Africa for use by HIV positive people. The main phytochemical component of AP is a norlignan glucoside, hypoxoside, and other relatively minor components have also been reported. A recent in vitro study reported the effects of AP extracts, hypoxoside and rooperol (the metabolite of hypoxoside) on human metabolic enzymes such as the cytochrome P450 (CYP450) group of enzymes and also on the transporter protein, p-glycoprotein (P-gp). This research focussed on investigating the clinical significance of those in vitro effects on the pharmacokinetics of efavirenz (EFV) in humans. EFV was chosen as the substrate drug because it is in first-line regimen of treatment of HIV/AIDS in South Africa, and also has been reported to be a substrate for the specific CYP isozymes, 3A4 and 2B6, in common with APs metabolic involvement with 3A4. A high performance liquid chromatography method with ultra-violet detection (HPLC-UV) for the quantitative determination of EFV in plasma was developed and successfully validated according to international standards with good reproducibility, accuracy, recovery, linear response and requisite sensitivity. The preparation of the plasma samples for analysis was effected by using a simple and rapid precipitation method, and the mobile phase consisted of readily available solvents. EFV in plasma samples was found to be stable under the relevant storage conditions studied. The oral dose of AP, administered as a freshly prepared traditional decoction, was standardised based on the hypoxoside content, and the quality of all the AP decoctions was analysed immediately prior to administration, using a validated HPLC-UV method. A single dose, two-phase sequential study was conducted over a period of 31 days in 10 healthy volunteers. The clinical study was approved by the Rhodes University Ethical Standards Committee, and all the participants agreed to the conditions of the study by giving their informed consent. On day 1 of the study, human subjects were administered a 600 mg EFV tablet and blood samples were collected before dosing and at various intervals over a period of 48 hr post dosing. From day 16, a traditionally prepared AP decoction was administered daily at a standardized dose of 15 mg/kg/day per subject until day 30. On day 29, volunteers were administered a single 600 mg dose of EFV as was done on day 1. Plasma samples were harvested immediately after blood sample collection and frozen at -80 ºC until assayed. Geometric mean ratios of relevant pharmacokinetic parameters, Cmax (maximum plasma concentration achieved following dosing) and AUC0-48 (area under the curve of a plot of drug plasma concentrations versus time representing the extent of absorption) of EFV before and after co-administration of 14 successive daily doses of AP were compared and evaluated to determine whether an interaction had occurred. All subjects completed the study and the geometric mean ratios of Cmax and AUC0-48 were 97.30 and 102.82 with corresponding 90% confidence intervals (CIs) of 78.81-120.14% and 89.04-118.80%, respectively. Whereas the acceptance criteria for the ratios of the AUCs fell within the preset 90% CIs indicating no interaction, the Cmax ratios fell outside the limits. Although the protocol was developed in accordance with the United States of America Food & Drug Administration’s Guidance for Drug Interactions, a priori stating that both criteria need to fall within the acceptance limits to indicate no interaction, an argument is presented to waive the Cmax requirement for the declaration of an interaction. As a result, the pharmacokinetic data generated during this study indicated that the effect of AP on the pharmacokinetics of EFV is not clinically significant. Hence, co-administration of AP is unlikely to affect the clinical use of EFV. In summary the objectives of this project were: 1. To develop and validate a suitable HPLC-UV method for the quantitative determination of EFV in plasma. 2. To perform a mini-validation of the determination of hypoxoside for use as a marker in the quality control and standardisation of AP decoctions. 3. To conduct a clinical interaction study in order to determine whether AP affects the pharmacokinetics of EFV following concurrent administration. 4. To apply the validated HPLC-UV method to determine plasma concentrations of EFV in plasma of human subjects. 5. To use appropriate statistical methods and treatments such as a non-compartmental pharmacokinetic analysis to determine the occurrence of an interaction.

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43

Croft, M. L. "Applications of human microdosing with accelerator mass spectrometry : assessment of ability to predict drug-drug interactions and determine the pharmacokinetics of enantiomers". Thesis, University of York, 2012. http://etheses.whiterose.ac.uk/4366/.

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In this thesis, new applications of microdosing were explored in two clinical trials. Methods were developed for the separation and quantification of 14C-labelled analytes in human plasma using two-dimensional HPLC and accelerator mass spectrometry (AMS). Caffeine, midazolam, tolbutamide and fexofenadine were quantified in plasma after administration of a 14C-labelled cassette microdose to human volunteers via a HPLC-AMS recovery constant method. Mean accuracy for all analytes was within 13% of the measured plasma concentration with precision of <20% CV, meeting recommended acceptance criteria for HPLC-AMS assays. Complete resolution of each analyte was demonstrated by two-dimensional HPLC. Pharmacokinetic data obtained after cassette microdose administration were in close agreement with those previously obtained after administration of therapeutic doses. Co-administration of the cassette microdose with known inhibitors of metabolism enzymes and transporters resulted in a significant (p<0.01) increase in the area under the concentration-time curve from time zero to infinity (AUC0-∞) for caffeine (x8.2), midazolam (x11.7), fexofenadine (x3.2) and tolbutamide (x1.8, p<0.05). Administration of a combined 11C and 14C-labelled verapamil microdose allowed distribution in the brain to be monitored by PET imaging, while simultaneously obtaining plasma pharmacokinetics by AMS. The separation of 14C-verapamil by two-dimensional HPLC and AMS analysis resulted in the individual pharmacokinetics of R- and S-verapamil being consistent with those reported after therapeutic doses. In addition, a significant difference in pharmacokinetic data obtained for the two enantiomers clearly showed the preferential clearance of S-verapamil. Data were accurate within 12% of the true value with precision of <18% CV. Pharmacokinetic data obtained after PET analysis were consistent with those obtained during AMS analysis, proving the concept of combining the two techniques in clinical studies and enabling maximum information to be achieved from one single study.

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44

Sadiq, Muhammad Waqas. "In Vivo Active Drug Uptake and Efflux at the Blood-Brain Barrier : With Focus on Drug Transport Interactions". Doctoral thesis, Uppsala universitet, Institutionen för farmaceutisk biovetenskap, 2012. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-180824.

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The blood-brain barrier (BBB) controls the movement of substances into and out of the brain. The tight junctions between endothelial cells and energy dependent transporters in the BBB influence rate and extent of drug distribution to the brain. The aim of this thesis was to study different methodological and pharmacokinetic aspects of drug transport at the BBB by characterizing possible active uptake and drug-drug interactions. Therefore, advanced tools for data acquisition and analysis were applied. The role of BBB transport in early drug development, with particular emphasis on in vitro-in vivo comparisons and species differences, was also investigated. Microdialysis in rats was used to study the BBB pharmacokinetics of oxymorphone, diphenhydramine (DPHM), oxycodone and morphine. Oxymorphone, DPHM and verapamil were all found to be actively taken up at the BBB, with brain to blood unbound drug ratios of 2, 5 and 2, respectively. The effect profile for oxycodone was successfully described using the modified M3 method for censored observations. In vitro experiments indicated a competitive interaction between DPHM and oxycodone on active uptake transport to the brain. No such interaction was observed in vivo due to much lower unbound concentrations achieved, compared with the in vitro Ki values. Active uptake of morphine at the BBB was not demonstrated even at very low concentrations as it was not possible to separate the active uptake transport process from active efflux by decreasing the morphine concentration. Mice carrying the human P-gp gene (hMDR1) were used to evaluate possible species differences in P-gp function. Differences were evident between the hMDR1 and normal mice in BBB penetration of various P-gp substrates and in the effect of blockers on P-gp function. Quantitative measurements of P-gp expression levels at the BBB and a comparison with human data are crucial for the future use of the hMDR1 model. In conclusion, this thesis reports active uptake of oxymorphone, DPHM and verapamil at the BBB. In vivo interaction of DPHM and oxycodone at the BBB was found not to be significant at therapeutic drug concentrations. Furthermore species differences were found between human and mouse P-gp function at the BBB.

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45

Karnik, Shreyas. "Mining Biomedical Literature to Extract Pharmacokinetic Drug-Drug Interactions". Thesis, 2014. http://hdl.handle.net/1805/3912.

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Indiana University-Purdue University Indianapolis (IUPUI)
Polypharmacy is a general clinical practice, there is a high chance that multiple administered drugs will interfere with each other, such phenomenon is called drug-drug interaction (DDI). DDI occurs when drugs administered change each other's pharmacokinetic (PK) or pharmacodynamic (PD) response. DDIs in many ways affect the overall effectiveness of the drug or at some times pose a risk of serious side effects to the patients thus, it becomes very challenging to for the successful drug development and clinical patient care. Biomedical literature is rich source for in-vitro and in-vivo DDI reports and there is growing need to automated methods to extract the DDI related information from unstructured text. In this work we present an ontology (PK ontology), which defines annotation guidelines for annotation of PK DDI studies. Using the ontology we have put together a corpora of PK DDI studies, which serves as excellent resource for training machine learning, based DDI extraction algorithms. Finally we demonstrate the use of PK ontology and corpora for extracting PK DDIs from biomedical literature using machine learning algorithms.

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46

Chen, Yun-An, e 陳韻安. "Pharmacokinetic Studies ofDrug-Drug Interactions by Renal Organic Anion Transporter Iin Rabbits". Thesis, 2009. http://ndltd.ncl.edu.tw/handle/97746703135254624600.

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碩士
臺北醫學大學
藥學研究所
97
Carrier-mediated processes, often referred to as transporters which located on the membrane, play key roles in the reabsorption and secretion of many endogenous and xenobiotic compounds by the kidney. In recent years, the specific roles of such transporters in drug disposition and drug-drug interactions become more important. The purpose of this study is to estimate the interaction of drugs with the organic anion transporter I (OATI) in the kidney. An accuracy, precision, simple and specific HPLC method was developed to detect the concentration of p-aminohippuric acid (PAH), ibuprofen (IBU) and indomethacin (INDO) in plasma. The drug-drug interaction evaluating of OATI was determined by combining dosing with same molar dose of I.V. of PAH (20mg/kg) and P.O. administration of single or multiple dose of IBU (21.38mg/kg) and INDO (37.08mg/kg) to rabbits. During single dose of INDO or IBU administration, the results were shown below: (1) INDO: significantly increased the AUC and Cmax by 8.42 to 11.33 fold (p<0.01) and decreased the CL by 6.94 fold (p<0.01). (2) PAH: slightly increased the AUC and slightly decreased the CL. (3) IBU: slightly increased the AUC and Cmax but significantly decreased the CL by 3.56 fold (p<0.01). (4) PAH: combination dosing with IBU slightly increased the AUC. In multiple dose studies, the results were shown below: (1) INDO: significantly increased the AUC and Cmax by 15.02 to 20.93 fold (p<0.01) and decreased the CL by 19.66 fold (p<0.01). (2) PAH: significantly increased the AUC by 2.07 fold (p<0.01) and decreased the CL by 1.94 fold (p<0.01). (3) IBU: slightly increased the AUC and Cmax but significantly decreased the CL by 5.53 fold (p<0.01). (4) PAH: slightly increased the AUC and slightly decreased the CL. The excretion of IBU in kidney (45%-75%) is equal with INDO (60%), but the tubular excretion of IBU was only 1% compared with 34.4% of INDO.This may result the difference of OATI effect. In comparison between single and multiple dose administration, the results showed the higher competition level in drug-drug interaction when INDO or IBU multiple administration. The OATI effect the elimination of IBU and INDO.

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47

Landersdorfer, Cornelia. "Modern pharmacokinetic-pharmacodynamic techniques to study physiological mechanisms of pharmacokinetic drug-drug interactions and disposition of antibiotics and to assess clinical relevance". Doctoral thesis, 2006. https://nbn-resolving.org/urn:nbn:de:bvb:20-opus-19340.

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There are numerous areas of application for which PKPD models are a valuable tool. We studied dose linearity, bone penetration and drug-drug interactions of antibiotics by PKPD modeling. Knowledge about possible saturation of elimination pathways at therapeutic concentrations is important for studying the probability of successful treatment of dosage regimens via MCS at various doses, other modes of administration, or both. We studied the dose linearity of flucloxacillin and piperacillin. For data analysis of the dose linearity studies, population PK modeling and MCS was used. Population PK has been reported to detect saturable elimination at lower doses, and to estimate BSV more precisely than the STS approach. The variability in PK and the expected variability in PD are combined in a MCS to predict the probability of successful treatment. Flucloxacillin showed no saturation of elimination at the studied doses of 500 mg and 1000 mg. Comparison of various dosage regimens showed, that only one third of the daily dose is needed with prolonged or continuous infusion to achieve the same probability of successful treatment as short-term infusions at the full dose. For serious infections with sensitive staphylococci that are treated with intravenous flucloxacillin, prolonged infusion and continuous infusion are an appealing treatment option. Contrary to flucloxacillin, renal elimination and to a lesser extent also nonrenal elimination of piperacillin were saturable at therapeutic concentrations. Renal clearance decreased by 24% (p = 0.02) after a dose of 3000 mg piperacillin compared to the 1500 mg dose. A model without saturable elimination predicted PTA expectation values that were 6 to 11% lower for high dose short-term infusions and 2 to 5% higher for low dose continuous infusions, compared to models with saturable elimination. These differences depend on the MIC distributions of the local hospital. However, more accurate estimates for the PTA expectation value can be obtained by including an existent saturable elimination pathway into the PK model. Developing a mechanistic model of an interaction allows one to predict the extent of the interaction for other doses of drug and inhibitor. We studied the interactions between gemifloxacin and probenecid, between ciprofloxacin, its metabolite M1 and probenecid, and between flucloxacillin and piperacillin. Mechanistic models for drug-drug interactions were developed by the STS approach. This approach directly accounts for the concentration dependence of an interaction and describes the full time course of an interaction. Probenecid significantly inhibited the renal elimination of gemifloxacin, ciprofloxacin and ciprofloxacin’s metabolite M1, and slightly decreased nonrenal clearance of gemifloxacin. Piperacillin significantly decreased renal and nonrenal clearance of flucloxacillin, but hardly vice versa. For all three interactions competitive inhibition of a capacity-limited renal elimination pathway was identified as the most likely mechanism. As those drugs are all actively secreted in the renal tubules, competitive interaction is physiologically reasonable. Probenecid had a lower affinity to the renal transporter than gemifloxacin, ciprofloxacin and M1. Due to its substantially higher concentrations, probenecid inhibited the elimination of the quinolones. The affinity of piperacillin for the renal transporter was 13 times higher compared to flucloxacillin. Piperacillin PK was only slightly affected by flucloxacillin. PK interactions with piperacillin are likely to occur also with other betalactam combinations. PK interactions may be useful to improve the PD profile of an antibiotic, however possibly increased risks for side effects (e.g. risk of rash for gemifloxacin and probenecid) have to be considered
Es gibt viele Anwendungsgebiete für die PKPD-Modelle wertvoll sind. In der vorliegenden Arbeit wurden Studien zu Dosislinearität, Knochenpenetration und Arzneistoffinteraktionen von Antibiotika mit Hilfe von PKPD-Modellen ausgewertet. Um die Wahrscheinlichkeit einer erfolgreichen Therapie durch Dosierungsregime mit verschiedenen Dosen, Verabreichungsmethoden oder beidem zu studieren, ist es nötig, Kenntnisse über möglicherweise vorhandene, bei therapeutischen Konzentrationen sättigbare Eliminationswege zu haben. Flucloxacillin und Piperacillin wurden auf ihre Dosislinearität untersucht. Zur Datenanalyse der Dosislinearitätsstudien wurden PopulationsPK-Modelle und MCS verwendet. Mit Hilfe von PopulationsPK kann eine sättigbare Elimination schon bei geringeren Dosen erkannt werden, und die Variabilität zwischen den Probanden kann genauer abgeschätzt werden als mit der STS-Methode. In einer MCS wird die Variabilität in der PK mit der erwarteten Variabilität in der PD kombiniert, um die Wahrscheinlichkeit einer erfolgreichen Behandlung vorherzusagen. Flucloxacillin zeigte bei 500 mg und 1000 mg keine Sättigung der Elimination. Ein Vergleich verschiedener Dosierungsregime zeigte, dass bei mehrstündiger oder kontinuierlicher Infusion im Vergleich zur Kurzzeitinfusion nur ein Drittel der Dosis benötigt wird, um die gleiche Wahrscheinlichkeit für eine erfolgreiche Behandlung zu erreichen. Für die Behandlung von schweren Infektionen durch empfindliche Staphylokokken ist mehrstündige oder kontinuierliche Infusion eine attraktive Möglichkeit. Im Gegensatz zu Flucloxacillin war die renale, und in einem geringeren Ausmaß auch die nicht-renale Elimination von Piperacillin bei therapeutischen Dosen sättigbar. Die renale Clearance war nach der 3000 mg Dosis um 24% (p = 0.02) verringert im Vergleich zur 1500 mg Dosis. Ein Modell ohne sättigbare Elimination sagte für hochdosierte Kurzzeitinfusionen 6 bis 11% niedrigere, und für niedrig dosierte kontinuierliche Infusion 2 bis 5% höhere Erwartungswerte für die Erfolgswahrscheinlichkeit voraus, als Modelle mit sättigbarer Elimination. Diese Unterschiede hängen von den minimalen Hemmkonzentrationen der Pathogene im jeweiligen Krankenhaus ab. Durch die Berücksichtigung eines vorhandenen sättigbaren Eliminationsweges im Modell kann der Erwartungswert für die Erfolgswahrscheinlichkeit genauer abgeschätzt werden. Die Entwicklung eines mechanistischen Interaktionsmodells ermöglicht es, das Ausmaß einer Interaktion für andere als die hier eingesetzten Dosen von Arzneistoff und Inhibitor vorherzusagen. In der vorliegenden Arbeit wurden die Interaktionen zwischen Gemifloxacin und Probenecid, sowie zwischen Ciprofloxacin, dessen Metaboliten M1 und Probenecid, und zwischen Flucloxacillin und Piperacillin untersucht. Die mechanistischen Interaktionsmodelle wurden mit Hilfe der STS-Methode entwickelt. Diese Methode bezieht die Konzentrationsabhängigkeit einer Interaktion direkt mit ein und beschreibt den vollständigen zeitlichen Verlauf der Interaktion. Probenecid hemmte die renale Elimination von Gemifloxacin, Ciprofloxacin und M1 signifikant und verringerte leicht die nicht-renale Clearance von Gemifloxacin. Piperacillin verminderte die renale und nicht-renale Clearance von Flucloxacillin signifikant. Für alle drei Interaktionen wurde eine kompetitive Inhibition eines sättigbaren renalen Eliminationsweges als wahrscheinlichster Mechanismus identifiziert. Da alle untersuchten Arzneistoffe aktiver renaler Sekretion unterliegen, ist eine kompetitive Interaktion auch physiologisch sinnvoll. Die Affinität von Probenecid zum renalen Transporter war niedriger als diejenige von Gemifloxacin, Ciprofloxacin und M1. Trotzdem wurde die Elimination der Chinolone durch Probenecid gehemmt, da Probenecid wesentlich höhere Konzentrationen erreichte. Die Affinität von Piperacillin zum renalen Transporter war 13 Mal höher als diejenige von Flucloxacillin. Die PK von Piperacillin wurde durch Flucloxacillin nur leicht beeinflusst. Es ist wahrscheinlich, dass Piperacillin auch mit anderen Betalaktamen PK-Interaktionen eingeht. PK-Interaktionen können zur Verbesserung des PD-Profils eines Antibiotikums genutzt werden, allerdings muss dabei auch das möglicherweise erhöhte Nebenwirkungsrisiko (z.B. Hautausschlag bei Probenecid und Gemifloxacin) bedacht werden

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48

Braz, Ana Sofia Pereira. "Review of drug interactions among the residents of a retirement home using different interaction databases". Master's thesis, 2016. http://hdl.handle.net/10451/35773.

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Trabalho Final de Mestrado Integrado, Ciências Farmacêuticas, Universidade de Lisboa, Faculdade de Farmácia, 2016
A polimedicação é um problema atual que coloca os doentes sobre um elevado risco de sofrerem interações medicamentosas. Isto verifica-se sobretudo na população idosa, que devido às comorbilidades e às mudanças fisiológicas associadas à idade, são especialmente vulneráveis a estas interações. Os mecanismos envolvidos nas interações entre fármacos podem afetar a farmacocinética ou a farmacodinâmica de um ou de ambos os fármacos em questão. O grande desafio da prática clínica é, portanto, conhecer as principais interações e saber como lidar com elas. Assim, os programas de screening de interações medicamentosas são uma mais valia para o clinico. Dois bons exemplos são os programas utilizados neste trabalho, Lexicomp Online e Drugs.com Interaction Checker, que permitiram avaliar as possíveis interações medicamentosas presentes num grupo de 30 doentes com idade superior a 65 anos, residentes de um lar de idosos. A utilização destes dois programas permitiu verificar algumas diferenças entre eles, que podem servir como fatores de escolha tendo em conta o objetivo pretendido.
Polipharmacy is a current problem that put patients under a serious risk of having drug interactions. This mostly occurs in elderly people because of their multimorbidity and age-related physiological changes, which make them especially vulnerable to interactions. The mechanisms involved in drugs interactions are associated with pharmacokinetic or pharmacodynamic alterations. The great challenge of clinical practice is to be aware of the most common interactions and know how to manage them. Therefore, drug-drug interactions screening programs are extremely useful for clinics. Two good examples are the programs used in this work, Lexicomp Online and Drugs.com Interaction Checker. They were used to evaluate the possible drug interactions in a group of 30 patients, aged more than 65 years old and living in a retirement home. The use of these two programs permitted to verify some differences between them that could be factors to help people choosing.

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49

"Mechanistic study of the pharmacokinetic herb-drug interactions between danshen-gegen formula and warfarin". 2014. http://repository.lib.cuhk.edu.hk/en/item/cuhk-1291818.

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Zhang, Zhen.
Thesis Ph.D. Chinese University of Hong Kong 2014.
Includes bibliographical references (leaves 215-249).
Abstracts also in Chinese.
Title from PDF title page (viewed on 15, November, 2016).

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50

Lai, Ming-Yen, e 賴明彥. "A Study on Pharmacokinetic Interactions between St. John’s wort and Indinavir in Rat Small Intestine". Thesis, 2004. http://ndltd.ncl.edu.tw/handle/67495966144012119710.

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碩士
國立臺灣大學
藥學研究所
93
In recent years, St. John''s wort (Hypericum perforatum, SJW) was used as an alternative therapy for the treatment of mild to moderate depression. Several active compounds from SJW have been isolated, including hypericin, pseudohypericin and hyperforin, etc. Besides, SJW may affect the activities of P-glycoprotein (Pgp) and cytochrome P450 (CYPs) in rats and human. In some clinical observations, SJW can reduce the plasma concentrations of indinavir, a HIV protease inhibitor, which is a substrate of CYP3A4 and Pgp. Therefore, a rat small intestine perfusion model was established for the investigation of the drug interactions between SJW and indinavir. In our study, oral administration of 300 mg/day SJW extracts to male Wistar rats for 15 days mostly reduced the water absorption ratio, water net flux, indinavir absorption ratio and indinavir absorption clearance even using four different perfusion flow rates, 0.05, 0.1, 0.5 and 1 mL/min. Besides, the plasma concentrations of indinavir in portal vein and hepatic vein were reduced significantly, and certain pharmacokinetic parameters of indinavir were also changed. However, no significant difference was observed for the mean hepatic extraction ratio (EH) and hepatic clearance (CLH) after SJW pretreatment. It is suggested that the activities of Pgp and CYPs might be involved in the drug interactions between SJW and indinavir. In the further study, the activity and protein expression of CYPs and Pgp in liver or small intestine will be clarified for the investigation of the drug interactions.

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