Academic literature on the topic 'Drug metabolism; Drug-drug interactions; Enzymes'
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Journal articles on the topic "Drug metabolism; Drug-drug interactions; Enzymes"
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Rekka, Eleni A., Panos N. Kourounakis, and Maria Pantelidou. "Xenobiotic Metabolising Enzymes: Impact on Pathologic Conditions, Drug Interactions and Drug Design." Current Topics in Medicinal Chemistry 19, no. 4 (April 11, 2019): 276–91. http://dx.doi.org/10.2174/1568026619666190129122727.
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Background: The biotransformation of xenobiotics is a homeostatic defensive response of the body against bioactive invaders. Xenobiotic metabolizing enzymes, important for the metabolism, elimination and detoxification of exogenous agents, are found in most tissues and organs and are distinguished into phase I and phase II enzymes, as well as phase III transporters. The cytochrome P450 superfamily of enzymes plays a major role in the biotransformation of most xenobiotics as well as in the metabolism of important endogenous substrates such as steroids and fatty acids. The activity and the potential toxicity of numerous drugs are strongly influenced by their biotransformation, mainly accomplished by the cytochrome P450 enzymes, one of the most versatile enzyme systems. Objective: In this review, considering the importance of drug metabolising enzymes in health and disease, some of our previous research results are presented, which, combined with newer findings, may assist in the elucidation of xenobiotic metabolism and in the development of more efficient drugs. Conclusion: Study of drug metabolism is of major importance for the development of drugs and provides insight into the control of human health. This review is an effort towards this direction and may find useful applications in related medical interventions or help in the development of more efficient drugs.
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Anderson, Gail D. "A Mechanistic Approach to Antiepileptic Drug Interactions." Annals of Pharmacotherapy 32, no. 5 (May 1998): 554–63. http://dx.doi.org/10.1345/aph.17332.
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OBJECTIVE: To describe the primary types of antiepileptic drug (AED) interactions by using a mechanistic approach. DATA SOURCES: A literature search was performed using MEDLINE and bibliographies of recent review articles and published abstracts. DISCUSSION: AEDs are associated with a wide range of drug interactions, including hepatic enzyme induction and inhibition and protein-binding displacement. Hepatic induction by AEDs affects the metabolism of a limited number of drugs with low therapeutic indices. Anticipation of induction interactions and careful clinical monitoring may alleviate potential problems. Most commonly used AEDs are eliminated through hepatic metabolism catalyzed by the cytochrome P450 (CYP) and uridine diphosphate glucuronosyltransferase (UGT) enzymes. Phenytoin, phenobarbital, and carbamazepine induce CYP and UGT enzymes. Lamotrigine is a weak inducer of UGT. Valproate is a broad-spectrum inhibitor of UGT enzymes, epoxide hydrolase, and CYP2C enzymes. Felbamate induces CYP3A4, but inhibits CYP2C19 substrates. Topiramate inhibits only CYP2C19 substrates. Ethosuximide, gabapentin, tiagabine, and vigabatrin are neither inducers nor inhibitors of drug metabolism. Hepatic enzyme inhibition usually occurs because of competition at the enzyme site. Knowledge of the specific metabolic enzymes involved in the metabolism of AEDs allows clinicians to predict potential interactions. CONCLUSIONS: By understanding the mechanisms of drug interactions, the pharmacist can play a key role in patient care by anticipating and preventing AED drug interactions.
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Klomp, Florian, Christoph Wenzel, Marek Drozdzik, and Stefan Oswald. "Drug–Drug Interactions Involving Intestinal and Hepatic CYP1A Enzymes." Pharmaceutics 12, no. 12 (December 11, 2020): 1201. http://dx.doi.org/10.3390/pharmaceutics12121201.
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Cytochrome P450 (CYP) 1A enzymes are considerably expressed in the human intestine and liver and involved in the biotransformation of about 10% of marketed drugs. Despite this doubtless clinical relevance, CYP1A1 and CYP1A2 are still somewhat underestimated in terms of unwanted side effects and drug–drug interactions of their respective substrates. In contrast to this, many frequently prescribed drugs that are subjected to extensive CYP1A-mediated metabolism show a narrow therapeutic index and serious adverse drug reactions. Consequently, those drugs are vulnerable to any kind of inhibition or induction in the expression and function of CYP1A. However, available in vitro data are not necessarily predictive for the occurrence of clinically relevant drug–drug interactions. Thus, this review aims to provide an up-to-date summary on the expression, regulation, function, and drug–drug interactions of CYP1A enzymes in humans.
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Thomas, Roger E. "Optimising Seniors’ Metabolism of Medications and Avoiding Adverse Drug Events Using Data on How Metabolism by Their P450 Enzymes Varies with Ancestry and Drug–Drug and Drug–Drug–Gene Interactions." Journal of Personalized Medicine 10, no. 3 (August 11, 2020): 84. http://dx.doi.org/10.3390/jpm10030084.
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Many individuals ≥65 have multiple illnesses and polypharmacy. Primary care physicians prescribe >70% of their medications and renew specialists’ prescriptions. Seventy-five percent of all medications are metabolised by P450 cytochrome enzymes. This article provides unique detailed tables how to avoid adverse drug events and optimise prescribing based on two key databases. DrugBank is a detailed database of 13,000 medications and both the P450 and other complex pathways that metabolise them. The Flockhart Tables are detailed lists of the P450 enzymes and also include all the medications which inhibit or induce metabolism by P450 cytochrome enzymes, which can result in undertreatment, overtreatment, or potentially toxic levels. Humans have used medications for a few decades and these enzymes have not been subject to evolutionary pressure. Thus, there is enormous variation in enzymatic functioning and by ancestry. Differences for ancestry groups in genetic metabolism based on a worldwide meta-analysis are discussed and this article provides advice how to prescribe for individuals of different ancestry. Prescribing advice from two key organisations, the Dutch Pharmacogenetics Working Group and the Clinical Pharmacogenetics Implementation Consortium is summarised. Currently, detailed pharmacogenomic advice is only available in some specialist clinics in major hospitals. However, this article provides detailed pharmacogenomic advice for primary care and other physicians and also physicians working in rural and remote areas worldwide. Physicians could quickly search the tables for the medications they intend to prescribe.
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Xie, Zhang, Zhang, and Yuan. "Metabolism, Transport and Drug–Drug Interactions of Silymarin." Molecules 24, no. 20 (October 14, 2019): 3693. http://dx.doi.org/10.3390/molecules24203693.
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Silymarin, the extract of milk thistle, and its major active flavonolignan silybin, are common products widely used in the phytotherapy of liver diseases. They also have promising effects in protecting the pancreas, kidney, myocardium, and the central nervous system. However, inconsistent results are noted in the different clinical studies due to the low bioavailability of silymarin. Extensive studies were conducted to explore the metabolism and transport of silymarin/silybin as well as the impact of its consumption on the pharmacokinetics of other clinical drugs. Here, we aimed to summarize and highlight the current knowledge of the metabolism and transport of silymarin. It was concluded that the major efflux transporters of silybin are multidrug resistance-associated protein (MRP2) and breast cancer resistance protein (BCRP) based on results from the transporter-overexpressing cell lines and MRP2-deficient (TR-) rats. Nevertheless, compounds that inhibit the efflux transporters MRP2 and BCRP can enhance the absorption and activity of silybin. Although silymarin does inhibit certain drug-metabolizing enzymes and drug transporters, such effects are unlikely to manifest in clinical settings. Overall, silymarin is a safe and well-tolerated phytomedicine.
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Rao Gajula, Siva Nageswara, Gangireddy Navitha Reddy, Dannarm Srinivas Reddy, and Rajesh Sonti. "Pharmacokinetic drug–drug interactions: an insight into recent US FDA-approved drugs for prostate cancer." Bioanalysis 12, no. 22 (November 2020): 1647–64. http://dx.doi.org/10.4155/bio-2020-0242.
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Pharmacokinetic drug–drug interaction is a significant safety and efficiency concern as it results in considerable concentration changes. Drug–drug interactions are a substantial concern in anticancer drugs that possess a narrow therapeutic index. These interactions remain as the principal regulatory obstacle that can lead to termination in the preclinical stage, restrictions in the prescription, dosage adjustments or withdrawal of the drugs from the market. Drug metabolizing enzymes or transporters mediate the majority of clinically relevant drug interactions. Cancer diagnosed aged patients use multiple medications and are more prone to significant drug–drug interactions. This review provides detailed information on clinically relevant drug–drug interactions resulting from drug metabolism by enzymes and transporters with a particular emphasis on recent FDA approved antiprostate cancer drugs.
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Bachmann, Kenneth A., and Jeffrey D. Lewis. "Predicting Inhibitory Drug—Drug Interactions and Evaluating Drug Interaction Reports Using Inhibition Constants." Annals of Pharmacotherapy 39, no. 6 (June 2005): 1064–72. http://dx.doi.org/10.1345/aph.1e508.
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OBJECTIVE: To review the use of inhibitory constants (Ki) determined from in vitro experiments in the prediction of the significance of inhibitory drug—drug interactions (DDIs). DATA SOURCES: Searches of MEDLINE (1966—August 2004) and manual review of journals, conference proceedings, reference textbooks, and Web sites were performed using the key search terms cytochrome P450, drug—drug interaction, inhibition constant, and Ki. STUDY SELECTION AND DATA EXTRACTION: All articles identified from the data sources were evaluated, and information deemed relevant was included for this review. DATA SYNTHESIS: The cytochrome P450 isoenzymes factor prominently in the explanation of numerous DDIs. Although the regulation of these enzymes by one drug can affect the pharmacokinetics of other drugs, the consequences may not necessarily be significant either in terms of pharmacokinetic or clinical outcomes. Yet, many DDI monographs originate as unconfirmed case reports that implicate the influence of one drug on the CYP-mediated metabolism of another, and these often uncorroborated mechanisms can eventually become regarded as dogma. One consequence of this process is the overprediction of potentially important DDIs. The pharmaceutical industry, Food and Drug Administration, and pharmaceutical scientists have developed a strategy for predicting the significance of inhibitory DDIs at the earliest possible stages of drug development based on a new chemical entity's Ki value, determined in vitro. CONCLUSIONS: We suggest that the use of Ki values of drugs purported to behave as CYP inhibitors be incorporated in the assessment of case reports that ascribe DDIs to inhibition of metabolism of one drug by another.
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Chadwick, Ben, Derek G. Waller, and J. Guy Edwards. "Potentially hazardous drug interactions with psychotropics." Advances in Psychiatric Treatment 11, no. 6 (November 2005): 440–49. http://dx.doi.org/10.1192/apt.11.6.440.
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Of the many interactions with psychotropic drugs, a minority are potentially hazardous. Most interactions are pharmacodynamic, resulting from augmented or antagonistic actions at a receptor or from different mechanisms in the same tissue. Most important pharmacokinetic interactions are due to effects on metabolism or renal excretion. The major enzymes involved in metabolism belong to the cytochrome P450 (CYP) system. Genetic variation in the CYP system produces people who are ‘poor’, ‘extensive’ or ‘ultra-rapid’ drug metabolisers. Hazardous interactions more often result from enzyme inhibition, but the probability of interaction depends on the initial level of enzyme activity and the availability of alternative metabolic routes for elimination of the drug. There is currently interest in interactions involving uridine diphosphate glucuronosyltransferases and the P-glycoprotein cell transport system, but their importance for psychotropics has yet to be defined. The most serious interactions with psychotropics result in profound sedation, central nervous system toxicity, large changes in blood pressure, ventricular arrhythmias, an increased risk of dangerous side-effects or a decreased therapeutic effect of one of the interacting drugs.
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Nemeroff, Charles B., Sheldon H. Preskorn, and C. Lindsay DeVane. "Antidepressant Drug-Drug Interactions: Clinical Relevance and Risk Management." CNS Spectrums 12, S7 (2007): 1–16. http://dx.doi.org/10.1017/s1092852900026043.
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AbstractMultiple medication use is a common phenomenon, especially in patients with comorbid conditions and those treated with psychiatric drugs such as antidepressants. Combination treatment may result in potentially harmful drug-drug interactions (DDIs). Results of DDIs range from nuisance side effects to serious adverse consequences. DDIs may also result in improved efficacy. Augmentation strategies, for example, are intentional therapeutic DDIs. Pharmacokinetic DDIs occur when a second drug alters the absorption, distribution, metabolism, or clearance of the first drug. Research has concentrated on the relative effects of antidepressants on cytochrome P450 enzymes and, more recently, on drug transporters as potential mediators of clinically important pharmacokinetic DDIs. The most common, clinically relevant pharmacokinetic DDIs involve alteration in oxidative drug metabolism. Pharmacodynamic DDIs occur when the effects of a second drug quantitatively or qualitatively alters those of the first drug. Pharmacodynamic DDIs are not typically studied in vivo because of the potential for a serious adverse effect. All antidepressants can interact pharmacodynamically with certain other drugs. The risk of harmful DDIs can be reduced by recognizing variables that affect dose-concentration-effect relationships. It is important for physicians to weigh the risks and benefits of potential DDIs against the risks that accompany timid or ineffective disease treatment.
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Yin, Jiayi, Fengcheng Li, Ying Zhou, Minjie Mou, Yinjing Lu, Kangli Chen, Jia Xue, et al. "INTEDE: interactome of drug-metabolizing enzymes." Nucleic Acids Research 49, no. D1 (October 12, 2020): D1233—D1243. http://dx.doi.org/10.1093/nar/gkaa755.
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Abstract Drug-metabolizing enzymes (DMEs) are critical determinant of drug safety and efficacy, and the interactome of DMEs has attracted extensive attention. There are 3 major interaction types in an interactome: microbiome–DME interaction (MICBIO), xenobiotics–DME interaction (XEOTIC) and host protein–DME interaction (HOSPPI). The interaction data of each type are essential for drug metabolism, and the collective consideration of multiple types has implication for the future practice of precision medicine. However, no database was designed to systematically provide the data of all types of DME interactions. Here, a database of the Interactome of Drug-Metabolizing Enzymes (INTEDE) was therefore constructed to offer these interaction data. First, 1047 unique DMEs (448 host and 599 microbial) were confirmed, for the first time, using their metabolizing drugs. Second, for these newly confirmed DMEs, all types of their interactions (3359 MICBIOs between 225 microbial species and 185 DMEs; 47 778 XEOTICs between 4150 xenobiotics and 501 DMEs; 7849 HOSPPIs between 565 human proteins and 566 DMEs) were comprehensively collected and then provided, which enabled the crosstalk analysis among multiple types. Because of the huge amount of accumulated data, the INTEDE made it possible to generalize key features for revealing disease etiology and optimizing clinical treatment. INTEDE is freely accessible at: https://idrblab.org/intede/
Dissertations / Theses on the topic "Drug metabolism; Drug-drug interactions; Enzymes"
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Maitland, Vivien. "Isozyme-specific induction of cytochrome P450 in rat hepatocyte cultures." Thesis, University of Aberdeen, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.302485.
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The aim of this study was to investigate the induction of CYP1A by DMSO, to determine whether DMSO induced other P450 isozymes (CYP2B) and to compare the effects of DMSO and another differentiating agent, sodium butyrate. Induction of CYP1A-dependent ethoxyresorufin-O-deethylase (EROD) was observed in the presence of increasing concentrations of DMSO. All concentration investigated (1%, 1.5% and 2%) caused induction (2-3 fold), and enhanced BA-induction of EROD. Enhancement of BA-induction was greater with 1% and 1.5% DMSO (2.5-3 fold over BA alone) than with 2% (1.8-fold). DMSO alone did not increase CYP1A1 RNA levels. Hepatocytes treated with BA and DMSO together exhibited a 1.3-fold greater increase in RNA levels than with BA alone. Western blotting indicated that CYP1A1 protein was increased by inducers (BA, DMSO and isosafrole), but that CYP1A2 was not. This indicates that the CYP1A1 isozyme is responsible for EROD activity in these cultures, and that the CYP1A2-induction mechanism is lost in rat hepatocytes cultured under the conditions of these experiments. This observation was confirmed by the lack of CYP1A2-dependent phenacetin-O-deethylase (POD) activity in culture. The substituted benzimidazole omeprazole has been shown to induce CYP1A isozymes in human hepatocyte cultures. In this study omeprazole was not effective in inducing EROD activity in rat hepatocytes or in vivo in the rat. This confirms that rat hepatocytes are not a good model for CYP1A induction in man. DMSO appears to be isozyme specific, since CYP2B-dependent pentoxyresorufin-O-dealkylase (PROD) activity was not increased by DMSO, and phenobarbitone (PB) induction of PROD was enhanced only slightly by DMSO on day 3 of culture (4-fold over control; 1.5-fold over PB alone). Sodium butyrate and DMSO were both shown to induce differentiation of rat hepatocyte, with maintenance of low level of γ-glutamyl transferase activity, and maintenance of a more rounded morphology.
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Wurden, Colleen J. "Metabolism of carbamazepine and inhibitory drug interactions /." Thesis, Connect to this title online; UW restricted, 2000. http://hdl.handle.net/1773/7977.
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Bradshaw, Jennifer Jean. "Isoflurane : interaction with hepatic microsomal enzymes." Doctoral thesis, University of Cape Town, 1992. http://hdl.handle.net/11427/27138.
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lsoflurane interacts with cytochrome P-450 in rat and human hepatic microsomes and the Δ6- and Δ5-desaturases in rat hepatic microsomes. The interaction of isoflurane with cytochrome P-450 results in its metabolism to fluoride ion and organofluorine metabolites. The cytochrome P-450 isozymes catalysing the defluorination of isoflurane were assessed in hepatic microsomes from phenobarbital-, β-naphthoflavone- and pregnenolone-16α-carbonitrilepretreated and untreated rats. One or more of the cytochrome P-450 isozymes induced by phenobarbital and pregnenolone-16α-carbonitrile appear to defluorinate isoflurane, but those induced by β-naphthoflavone do not. From a comparison of the extent of defluorination of isoflurane in hepatic microsomes from phenobarbital- and pregnenolone-16α-carbonitrile-pretreated rats, and their Kₘ and Vₘₐₓ values, it appears that isoflurane is defluorinated by one or more isozymes induced by both phenobarbital and pregnenolone-16α-carbonitrile. The major isozyme is probably cytochrome P-450PCN1. The metabolites of isoflurane were identified in human and phenobarbital-induced rat hepatic microsomes. In microsomes from phenobarbital-pretreated rats, isoflurane is metabolised to fluoride ion and trifluoroacetaldehyde; trifluoroacetic acid is not produced in measureable amounts. The trifluoroacetaldehyde produced binds to microsomal constituents. In human hepatic microsomes, the organofluorine metabolite is identified as trifluoroacetic acid. It is proposed that isoflurane is metabolised by different pathways in human and phenobarbital-induced rat hepatic microsomes. The interaction of isoflurane with the cyanide-sensitive factors was assessed by several criteria. Firstly, using the reoxidation of cytochrome b₅ as an index of fatty acid desaturase activity, isoflurane appears to interact with the Δ6- and/or Δ5-desaturases, but not the Δ9-desaturase. Secondly, these results were confirmed and clarified by the use of direct assays to measure the fatty acid desaturase activity. Using the direct assay, we confirmed that isoflurane did not inhibit the Δ9-desaturase and inhibited Δ6-desaturation of linoleic acid, but not the Δ6-desaturation of α-linolenic acid. The inhibition of the Δ6-desaturation of linoleic acid occurred at low millimolar concentrations of isoflurane. lsoflurane inhibits the Δ5-desaturation of eicosa-8, 11, 14-trienoic acid to a small extent which is only apparent at much higher concentrations of isoflurane than that which inhibits the Δ6-desaturase. Further studies focussed on measurement of the activity of Δ6-desaturase in order to attempt to study the kinetics of the inhibition of the Δ6-desaturase by isoflurane: Δ6-desaturase activity was assessed using hepatic microsomes as the source of the enzyme and linoleic acid as substrate precursor. In the course of these studies, we identified a number of factors that affected the apparent activity of the Δ6-desaturase in hepatic microsomes. These included significant levels of endogenous substrate and competing reactions in the hepatic microsomes. Endogenous substrate levels were quantified and corrected for. We then resorted to computer modelling to extract the kinetics of the Δ6-desaturase free of contributions from acyl-CoA synthetase and lysophospholipid acyltransferase, as well as enzyme decay. The kinetics of isoflurane inhibition of the Δ6-desaturase were then superimposed and studied by computer modelling.
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Uusitalo, J. (Jouko). "The role of drug metabolism in drug discovery and development:case ospemifene." Doctoral thesis, Oulun yliopisto, 2015. http://urn.fi/urn:isbn:9789526210223.
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Abstract Drug metabolism is one of the most important events a drug faces after administration. Traditionally, drug metabolism has only been considered as a major clearance and elimination step in the pharmacokinetics of a drug. However, drug metabolism is also one of the important factors behind safety and toxicity issues in drug discovery and development. Some of the mechanisms behind metabolism-related toxicity we do understand well while others, especially the role of reactive metabolites, need further research. The thesis reviews the role of drug metabolism in the drug discovery and development process from the point of view of metabolism and metabolites. Special emphasis is put on reviewing the metabolism behind human toxicity and safety, and the roles of circulating and reactive metabolites in particular. Ospemifene is a nonsteroidal selective estrogen receptor modulator recently approved for the treatment of vulvar and vaginal atrophy in postmenopausal women with moderate to severe dyspareunia. The present study characterized the in vitro and in vivo metabolism and potential drug interactions of ospemifene. The principal human metabolites were identified and the adequacy nonclinical animal exposure was evaluated. The major human cytochrome P450 enzymes involved in the formation of principal metabolites were also identified and the clinical consequences assessed. Finally, the interaction potential of ospemifene as a cytochrome P450 enzyme inducer or inhibitor was investigated. As a result, ospemifene was considered to be safe drug from a metabolic interaction point of view. This study was part of the drug development program of ospemifene and practically all of the in vitro study data were included in the marketing authorization application of ospemifene. Ospemifene was also a case molecule in the development of new methodologies to study drug metabolism and drug-drug interactionsTiivistelmä Lääkeainemetabolia on lääkeaineen farmakokinetiikassa tärkeä puhdistuma- ja eliminaatioaskel, jonka rooli on ymmärretty varsin hyvin. Lääkeainemetabolialla on myös merkittävä vaikutus lääkeaineen toksisuuteen ja lääkkeen käytön turvallisuuteen. Osa lääkeainemetaboliaan liittyvistä toksisuusmekanismeista selvitetty hyvin, mutta erityisesti reaktiivisiin metaboliitteihin liittyvä osa vaatii vielä tutkimusta. Tämän työn kirjallisuusosassa katselmoidaan lääkeainemetabolian merkitystä lääkekehitysprosessissa painottaen erityisesti lääkeainemetabolian sekä reaktiivisten ja verenkierrossa kiertävien metaboliatuoteiden vaikutusta toksisuuteen ihmisellä ja merkitystä turvalliseen lääkkeiden käyttöön. Ospemifeeni on uusi ei-steroidinen selektiivinen estrogeenireseptorimodulaattori, joka on hyväksytty yhdynnänaikaisesta kivusta kärsivien postmenopausaalisten naisten vulvan ja vaginan limakalvojen kuivumisen hoitoon. Tässä tutkimuksessa selvitettiin ospemifeenin lääkeainemetaboliaa ihmisellä ja koe-eläimillä sekä mahdollisia lääkeinteraktioita. Tutkimuksessa tunnistettiin tärkeimmät metaboliitit ihmisellä ja arvioitiin eläinkokeissa käytettyjen koe-eläinten altistumisen kattavuus niille. Työssä selvitettiin myös tärkeimmät päämetaboliitteja katalysoivat sytokromi P450 -entsyymit ja arvioitiin löydösten kliinistä merkitystä. Lisäksi tutkittiin aiheuttaako ospemifeeni lääkeinteraktioita muille lääkeaineille indusoimalla tai inhiboimalla sytokromi P450 -entsyymejä. Tutkimustulosten perusteella ospemifeenia voidaan pitää lääkeainemetabolian suhteen turvallisena lääkkeenä. Tämä tutkimus oli osa ospemifeenin lääkekehitysohjelmaa ja käytännössä kaikki tutkimustyön in vitro -tietoaineisto oli mukana ospemifeenin myyntilupa-hakemuksissa lääketurvallisuusviranomaisille. Ospemifeenia käytettiin tutkimustyön aikana myös yhtenä esimerkkimolekyylinä kehitettäessä uusia menetelmiä lääkeainemetabolian ja lääkeinteraktioiden tutkimiseen
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Turpeinen, M. (Miia). "Cytochrome P450 enzymes—in vitro, in vivo, and in silico studies." Doctoral thesis, University of Oulu, 2006. http://urn.fi/urn:isbn:9514282205.
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Abstract
Metabolism is a major determinant of the pharmacokinetic properties of most drugs and is often behind bioavailability problems, drug-drug interactions, and metabolic idiosyncrasies. Cytochrome P450 (CYP) enzymes are a superfamily of microsomal hemoproteins catalysing the metabolic reactions of several exogenous compounds. The majority of crucial steps within drug metabolism are in connection with CYP enzymes.
In the present study, in vivo, in vitro, and in silico approaches were applied and characterised to evaluate the effects of chemical entities on CYP-mediated metabolism. CYP2B6 was used as a target enzyme for these studies.
For evaluation of the CYP inhibition potential of new chemical entities, a novel in vitro test system utilising the n-in-one approach was developed. This method proved to be robust and applicable to screening purposes. Validation of the n-in-one assay was done by comparing its performance to commonly used in vitro techniques using six structurally diverse drugs. All assay types yield remarkably similar results with the majority of the CYP forms tested.
Several chemicals were screened in vitro and in silico in order to find potent and selective chemical inhibitors for CYP2B6. Ticlopidine, thioTEPA and 4-(4-chlorobenzylpyridine) were found to be highly effective inhibitors of CYP2B6. The selectivity of thioTEPA proved to be very high, whereas ticlopidine and 4-(4-chlorobenzylpyridine) also inhibited other CYPs. At a concentration level of 1 μM for ticlopidine and 0.1 μM for 4-(4-chlorobenzylpyridine), the inhibitory effect towards other CYPs was negligible.
Due to wide clinical use and relevance, clopidogrel and ticlopidine were selected for further in vivo interaction studies. Both clopidogrel and ticlopidine significantly inhibited the CYP2B6-catalysed bupropion hydroxylation and patients receiving either clopidogrel or ticlopidine are likely to need dose adjustments when treated with drugs primarily metabolised by CYP2B6. The effect of impaired kidney function on CYP2B6 activity and on bupropion pharmacokinetics was also explored. In patients with kidney disease, the bupropion AUC and Cmax were significantly higher and the apparent oral clearance of bupropion was notably lower compared to healthy controls.
The present results indicate that the in silico and in vitro methods used are helpful in predicting in vivo drug-drug interactions. The effective utilisation of these models in the early phases of drug discovery could therefore help to target the in vivo studies and to eliminate metabolically unfavourable drug candidates.
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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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Vicente, David Gil Marques Borrero. "An overview of the role of cytochrome P450 enzyme system in food-drug interactions and possible applications in veterinary medicine." Bachelor's thesis, Universidade Técnica de Lisboa. Faculdade de Medicina Veterinária, 2009. http://hdl.handle.net/10400.5/1003.
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Dissertação de Mestrado Integrado em Medicina VeterináriaCytochrome P450 enzymes (CYP) are hemoproteins belonging to the group of monooxygenases and one of the main enzymatic systems responsible for drug metabolism. In the present study, in vitro approach was applied to evaluate the relation of CYP-catalyzed activities between human, rabbit, minipig and mouse, using single substrate assays (MultiCYP 7-ethoxycoumarin 0-deethylase (ECOD), CYP1A1/2 7-ethoxyresorufin 0- deethylase (EROD), CYP2A6 coumarin 7-hydroxylase (COH), CYP3A4 midazolam 1- hydroxylase (OH-MDZ), and CYP2E1 chlorzoxazone 6-hydroxylase (OH-CLZ)). It was also studied plant extracts (Pinus sylvestris, Angelica archangelica, Mentha sp., Citrus grandis) and phytochemicals (8-Hydroxybergapten, 5,6-dihydroxyangelicin, α, β-Thujone, α-Thujone, angelicin, bergamottin, bergapten, bergaptol, cnidilin, imperatorin, isobergapten, isopimpinellin, lanatin, phellopterin, psoralen, sphondin, xanthotoxin) as potential inhibitors in CYP-related activities of hepatic human microsomes (CYP1A1/2 (EROD), CYP2A6 (COH), CYP3A4 (OH-MDZ)). This study showed that the lowest ECOD activity was detected in humans and there was no similarity between other species. CYP1A1/2 showed equivalent activities. The highest CYP activities in humans were found for CYP2A6 and CYP3A4. In CYP2E1 activity, two similar groups were recognized: human and mouse versus rabbit and minipig. EROD reaction was the most inhibited CYP-mediated reaction. COH reaction was inhibited by few compounds. The highest inhibition was detected among angular furocoumarins. Linear furocoumarins group had the lower inhibitory concentration of CYP3A4. Thujone showed weak inhibition of CYP activities.
RESUMO - As enzimas do sistema citocromo P450 (CYP) são hemoproteinas pertencentes ao grupo das monoxigenases e um dos principais sistemas enzimáticos responsáveis pela metabolização de fármacos. Neste estudo foi avaliada a relação da actividade catalítica de diferentes CYPs entre humanos, coelhos, minipig e murganhos, recorrendo a substratos como sondas individuais in vitro para mensurar reacções especificas (MultiCYP 7-etoxicumarina 0-deetilase (ECOD), CYP1A1/2 7-etoxiresorufina 0-deetilase (EROD), CYP2A6 cumarina 7-hidroxilase (COH), CYP3A4 midazolam 1-hidroxilase (OH-MDZ), e CYP2E1 clorozoxazona 6-hidroxilase (OH-CLZ)). Também foram estudados extractos de plantas (Pinus sylvestris, Angelica archangelica, Mentha sp., Citrus grandis) e fitoquímicos (8-hidroxibergaptem, 5,6-dihidroxiangelicina, α, β-tujona, α-tujona, angelicina, bergamottin, bergapteno, bergaptol, cnidilina, imperatorina, isobergapteno, isopimpinelina, lanatin, felopterina, psoraleno, sphondin, xantotoxina) como potenciais inibidores da actividade catalítica dos CYPs microssomais hepáticos humanos (CYP1A1/2 (EROD), CYP2A6 (COH), CYP3A4 (OH-MDZ)). Neste estudo não foram detectadas actividades similires entre espécies na reacção ECOD e a actividade mais baixa foi detectada nos humanos. A reacção EROD dos CYP1A1/2 demonstrou actividades similares entre as diferentes espécies. As maiores actividades cataliticas verificadas nos humanos correspondem aos CYP2A6 e CYP3A4. No estudo da reacção do CYP2E1 foram determinados dois grupos distintos com actividades cataliticas similares: 1) humanos e murganhos, 2) coelhos e minipigs. No estudo de potenciais inibidores dos CYPs, a reacção EROD foi a mais inibida. Pelo contrário, a reacção COH foi inibida por poucos compostos. A maioria das inibições ocorreu por exposição a furocumarinas angulares. O grupo de furocumarinas lineares teve a menor concentração inibitória da reacção OH-MDZ do CYP3A4. Os fitoquímicos α, β-tujona e α- tujona demonstraram ter um fraco poder inibitório na actividade dos CYPs analisados.
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Kabulski, Jarod L. "Development of Au-immobilized P450 platform for exploring the effect of oligomer formation on P450-mediated metabolism for In vitro to In vivo drug metabolism predictions." Morgantown, W. Va. : [West Virginia University Libraries], 2010. http://hdl.handle.net/10450/10892.
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Thesis (Ph. D.)--West Virginia University, 2010.Title from document title page. Document formatted into pages; contains xiv, 180 p. : ill. (some col.). Includes abstract. Includes bibliographical references.
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Habenschus, Maísa Daniela. "Estudos de inibição das enzimas do citocromo P450 pelo produto natural (-)-grandisina utilizando microssomas hepáticos de humanos." Universidade de São Paulo, 2016. http://www.teses.usp.br/teses/disponiveis/59/59138/tde-06072016-095943/.
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A (-)- grandisina (GRA) é um produto natural da classe das lignanas e é encontrada em muitas espécies de plantas das regiões Norte e Nordeste do Brasil. Por apresentar diversas propriedades biológicas, como atividade tripanocida, anti-inflamatória, antinociceptiva, e principalmente atividade antileucêmica e antitumoral contra tumores de Ehrlich, a GRA pode ser considerada um potencial candidato a fármaco. Porém, para que a GRA se torne um fármaco são necessárias diversas etapas de estudos, incluindo estudos pré-clínicos de interações medicamentosas (DDI). As DDI ocorrem principalmente devido a inibições diretas e tempo-dependentes das enzimas do citocromo P450 (CYP450), uma superfamília de enzimas responsável por metabolizar cerca de 75% dos fármacos em uso. Os estudos pré-clínicos de DDI envolvem o conhecimento do potencial inibitório do candidato a fármaco sobre essas enzimas e esses estudos podem ser realizados empregando diversos modelos in vitro, como, por exemplo, microssomas hepáticos de humanos (HLM). Assim, nesse estudo foi avaliado o efeito inibitório da GRA sobre a atividade das principais isoformas do CYP450 e também foram determinadas as isoformas que contribuem para a formação dos metabólitos da GRA. Os resultados demonstraram que múltiplas isoformas participam da formação dos metabólitos da GRA, com destaque para a CYP2C9, que participa da formação de todos os metabólitos. Em relação aos estudos de inibição, foi possível concluir que a GRA é um inibidor fraco da CYP1A2 e CYP2D6, com valores de IC50 maiores do que 200 µM e 100 µM, respectivamente, e um inibidor moderado e competitivo da CYP2C9, com IC50 igual a 40,85 µM e Ki igual a 50,60 µM. Para a CYP3A4 o potencial inibitório da GRA foi avaliado utilizando dois substratos distintos. A GRA demonstrou ser tanto um inibidor dose-dependente moderado e competitivo dessa isoforma, quanto um inibidor tempo-dependente baseado em mecanismo com potencial de inativação equiparável ao do irinotecano, inibidor baseado em mecanismo clinicamente significativo. Utilizando a nifedipina como substrato os valores de IC50 e Ki foram 78,09 µM e 48,71 µM, respectivamente. Já os valores dos parâmetros cinéticos de inativação foram KI= 6,40 µM, kinact= 0,037 min-1 e Clinact= 5,78 mL min-1 µmol-1. Para os ensaios empregando o midazolam os valores de IC50 e Ki foram 48,87 µM e 31,25 µM, respectivamente, e os valores dos parâmetros cinéticos de inativação foram KI= 31,53 µM, kinact= 0,049 min-1 e Clinact= 1,55 mL min-1 µmol-1. Com relação a CYP2E1, por sua vez, foi possível observar que a GRA tem capacidade de aumentar a atividade dessa isoforma significativamente a partir da concentração de 4 µM. Portanto, conclui-se que não há risco da GRA apresentar interações medicamentosas com fármacos metabolizados pela CYP1A2 e CYP2D6, enquanto que para a CYP2C9, apesar da GRA ser um inibidor moderado dessa isoforma, o risco é baixo. Já para medicamentos metabolizados pela CYP2E1 e CYP3A4 o risco de DDI existe e isso deve ser cuidadosamente monitorado in vivo, principalmente porque a CYP3A4 é a isoforma responsável por catalisar o metabolismo da maioria dos fármacos.(-)-grandisin (GRA) is a lignanic natural product found in many species of plants from North and Northeast of Brazil. This compound has several biological properties, such as trypanocide, anti-inflammatory, antinociceptive, antileukemia activity and antitumor activity against Ehrlich tumor. Because of these biological properties, GRA is considered a potential drug candidate, however, before becoming a new drug, GRA has to undergo various tests, including preclinical drug-drug interactions (DDI) studies. Most of the times, DDI occur because of direct and time-dependent inhibitions of cytochrome P450 (CYP450) enzymes, an enzyme superfamily responsible for metabolizing the vast majority of drugs administered. Preclinical drug-drug interactions studies involve the evaluation of the potential of a drug candidate to inhibit this superfamily of enzymes and these studies can be conducted using in vitro models, such as human liver microsomes (HLM). Therefore, in this project, the inhibitory effect of GRA on the activity of some CYP450 isoforms was evaluated and the isoforms that catalyze the formation of GRA\'s metabolites were also determined. Results showed that multiple CYP450 isoforms participate in the GRA\'s metabolites formation, highlighting CYP2C9, which catalyzes the formation of all metabolites. The inhibition studies showed that GRA is a weak inhibitor of CYP1A2 and CYP2D6, with IC50 values greater than 200 µM and 100 µM, respectively, and a moderate and competitive inhibitor of CYP2C9, with IC50 value equal to 40.85 µM and Ki value equal to 50.60 µM. The capability of GRA to inhibit CYP3A4 was evaluated using two different substrates. GRA showed to be a moderate and competitive dose- dependent inhibitor of this isoform and also a mechanism-based time-dependent inhibitor with potential of inactivation comparable to irinotecan, a clinically significant mechanism-based inhibitor. IC50 and Ki values obtained using nifedipine as substrate were 78.09 µM and 48.71 µM, respectively, and inactivation kinetics parameters were KI= 6.40 µM, kinact= 0,037 min-1 e Clinact= 5.78 mL min-1 µmol-1. On the other hand, IC50 and Ki values using midazolam as substrate were 48.87 µM and 31.25 µM, respectively, and the values of inactivation kinetics parameters were KI= 31.53 µM, kinact= 0,049 min-1 and Clinact= 1.55 mL min-1 µmol-1. With respect to CYP2E1, it was observed that GRA increases its activity significantly from a concentration of 4 µM. Therefore, it is possible to conclude that there is no risk of DDI between GRA and drugs metabolized by CYP1A2 and CYP2D6, while for CYP2C9, although GRA is a moderate inhibitor of this isoform, the risk is low. Finally, for drugs metabolized by CYP3A4 and CYP2E1 there is risk of DDI and this should be carefully monitored in humans, mainly because CYP3A4 is an isoform responsible for catalyzing the metabolism of most drugs in use.
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Nguyen, San. "Inhibitory Properties of Functional Food Plants on CYP Enzymes and Cree Traditional Medicines on Aldose Reductase." Thèse, Université d'Ottawa / University of Ottawa, 2011. http://hdl.handle.net/10393/20070.
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This thesis examines the cytochrom P450 (CYP) drug metabolizing enzyme inhibition and antimicrobial properties of 46 common food plants available in the Canadian Market and the inhibitory properties of 17 traditional Cree antidiabetic medicines on aldose reductase. Inhibitory activity profiles of CYP 3A4, 3A5, 3A7 and 2D6 were created for the 46 samples. The most active plants in the CYP inhibition assay were the spices, belonging to the Apiaceae and Lamiaceae. Similarly, the most active plants in the antimicrobial assay were also the Apiaceae and Lamiaceae. Swine lens homogenate was tested as a novel model for the aldose reductase inhibition assay. Several Cree plants selected for the aldose reductase study showed a high activity, primarily in samples which also contained high levels of phenolics. A positive correlation was observed between total phenolics content and aldose reductase inhibition r2=0.44, p=0.05. Crude extracts of Rhododendron groenlandicum exhibited inhibitory activities of 35.11 ± 0.16 %. The subfractionation and HPLC analysis of R. groenlandicum revealed high levels of phenolics compounds including, catechin, epicatechin, quercetin and quercetin glycosides. This study found that medicinal and food plants contain phytochemicals that may have both beneficial and detrimental biological effects.Nous avons étudié dans cette thèse les capacités de 46 plantes comestibles, disponibles sur le marché canadien, à inhiber le cytochrome P450 (CYP), enzyme responsable du métabolisme des médicaments, les propriétés antimicrobiennes, et les propriétés inhibitrices de l'aldose réductase à partir de 17 médicaments antidiabétiques traditionnellement utilisés par les Cris. Les profils de l'activité inhibitrice du CYP 3A4, 3A5, 3A7 et 2D6 ont été réalisés pour les 46 plantes à l'étude. Les plantes les plus actives dans le test d'inhibition du CYP furent les épices, plantes appartenant aux familles des Apiaceae et Lamiaceae. De même, les plantes les plus actives dans le bioessai antimicrobien furent aussi les plantes de ces deux mêmes familles. Un homogénat de cristallin de porc a été utilisé comme modèle nouveau pour le test d'inhibition de l'aldose réductase. Plusieurs plantes, utilisées par la nation Cri, qui ont été sélectionnées pour l'étude ont montré une forte activité inhibitrice de l’aldose réductase, principalement dans les échantillons qui contenaient des teneurs élevées en composés phénoliques. Une corrélation positive a été observée entre la teneur totale en composés phénoliques et l'inhibition de l'aldose réductase (r2 = 0.44, p = 0.05). Des extraits bruts de Rhododendron groenlandicum ont montré des activités inhibitrices de 35.11 ± 0.16%. Le sous-fractionnement et l'analyse HPLC de R. groenlandicum ont aussi révélé des teneurs élevées des composés phénoliques, incluant la catéchine, l'épicatéchine, la quercétine et les glycosides de quercétine. Cette étude a montré que les plantes médicinales et alimentaires contiennent des composés phytochimiques qui peuvent avoir à la fois des effets biologiques bénéfique et préjudiciable.
Books on the topic "Drug metabolism; Drug-drug interactions; Enzymes"
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Pang, K. Sandy. Enzyme- and transporter-based drug-drug Interactions: Progress and future challenges. New York: Springer, 2010.
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Giralt, Ernest, Mark Peczuh, and Xavier Salvatella. Protein surface recognition: Approaches for drug discovery. Chichester, West Sussex: John Wiley & Sons, 2011.
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Cozza, Kelly L. Concise guide to the cytochrome P450 system: Drug interaction principles for medical practice. Washington, DC: American Psychiatric Pub., 2001.
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Lyubimov, Alexander V. Encyclopedia of drug metabolism and interactions. Hoboken, N.J: Wiley, 2012.
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Enzyme kinetics in drug metabolism: Fundamentals and applications. New York: Humana Press, 2014.
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T, Walsh Carol, and Schwartz-Bloom Rochelle D, eds. Pharmacology: Drug actions and reactions. 6th ed. New York: Parthenon Pub. Group, 2000.
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T, Walsh Carol, and Schwartz Rochelle D, eds. Pharmacology: Drug actions and reactions. 5th ed. New York: Parthenon Pub. Group, 1996.
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Methods for studying nucleic acid/drug interactions. Boca Raton: Taylor & Francis, 2012.
Find full textBook chapters on the topic "Drug metabolism; Drug-drug interactions; Enzymes"
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Louie, Steven W., and Magang Shou. "Drug-Metabolizing Enzymes, Transporters, and Drug-Drug Interactions." In Mass Spectrometry in Drug Metabolism and Disposition, 83–149. Hoboken, NJ, USA: John Wiley & Sons, Inc., 2011. http://dx.doi.org/10.1002/9780470929278.ch4.
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Houston, J. Brian, and Aleksandra Galetin. "In Vitro Techniques to Study Drug–Drug Interactions of Drug Metabolism: Cytochrome P450." In Enzyme- and Transporter-Based Drug-Drug Interactions, 169–215. New York, NY: Springer New York, 2009. http://dx.doi.org/10.1007/978-1-4419-0840-7_7.
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Kadlubar, Susan, and Fred F. Kadlubar. "Enzymatic Basis of Phase I and Phase II Drug Metabolism." In Enzyme- and Transporter-Based Drug-Drug Interactions, 3–25. New York, NY: Springer New York, 2009. http://dx.doi.org/10.1007/978-1-4419-0840-7_1.
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Yeung, Catherine K., Ping Zhao, Danny D. Shen, and Kenneth E. Thummel. "Drug Disposition and Drug–Drug Interactions: Importance of First-Pass Metabolism in Gut and Liver." In Enzyme- and Transporter-Based Drug-Drug Interactions, 415–35. New York, NY: Springer New York, 2009. http://dx.doi.org/10.1007/978-1-4419-0840-7_17.
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Hachad, Houda, Isabelle Ragueneau-Majlessi, and René H. Levy. "Management of Drug Interactions of New Drugs in Multicenter Trials Using the Metabolism and Transport Drug Interaction Database©." In Enzyme- and Transporter-Based Drug-Drug Interactions, 371–86. New York, NY: Springer New York, 2009. http://dx.doi.org/10.1007/978-1-4419-0840-7_15.
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Oesch, F., F. Fähndrich, H. R. Glatt, B. Oesch-Bartlomowicz, K. L. Platt, and D. Utesch. "Use of Mechanistic Information for Adequate Metabolic Design of Genotoxicity Studies and Toxicological Interactions of Drugs and Environmental Chemicals." In Molecular Aspects of Oxidative Drug Metabolizing Enzymes, 397–409. Berlin, Heidelberg: Springer Berlin Heidelberg, 1995. http://dx.doi.org/10.1007/978-3-642-79528-2_17.
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D’Arcy, P. F. "Drug Interactions and Drug-Metabolising Enzymes." In Mechanisms of Drug Interactions, 151–71. Berlin, Heidelberg: Springer Berlin Heidelberg, 1996. http://dx.doi.org/10.1007/978-3-642-61015-8_5.
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Ward, L., P. Butler, and R. Riley. "Metabolism Drug Interactions." In The ADME Encyclopedia, 1–11. Cham: Springer International Publishing, 2021. http://dx.doi.org/10.1007/978-3-030-51519-5_89-1.
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Chang, Thomas K. H. "Drug-Metabolizing Enzymes." In Handbook of Drug-Nutrient Interactions, 85–117. Totowa, NJ: Humana Press, 2009. http://dx.doi.org/10.1007/978-1-60327-362-6_4.
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Khojasteh, Siamak Cyrus, Harvey Wong, and Cornelis E. C. A. Hop. "Drug Metabolizing Enzymes." In Drug Metabolism and Pharmacokinetics Quick Guide, 17–46. New York, NY: Springer New York, 2011. http://dx.doi.org/10.1007/978-1-4419-5629-3_2.
Full textConference papers on the topic "Drug metabolism; Drug-drug interactions; Enzymes"
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Ma, Liang, Jeremy Barker, Changchun Zhou, Biaoyang Lin, and Wei Li. "A Perfused Two-Chamber System for Anticancer Drug Screening." In ASME 2010 International Manufacturing Science and Engineering Conference. ASMEDC, 2010. http://dx.doi.org/10.1115/msec2010-34326.
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A cell culture microfluidic device has been developed to test the cytotoxicity of anticancer drugs while reproducing multi-organ interactions in vitro. Cells were cultured in separate chambers representing the liver and tumor. The two chambers were connected through a channel to mimick the blood flow. Glioblastoma (GBM) cancer cells (M059K) and hepatoma cells (HepG2) were cultured in the tumor and the liver chambers, respectively. The cytotoxic effect of cancer treatment drug Temolozomide (TMZ) was tested using this two chamber system. The experimental results showed that with the liver cells, the cancer cells showed much higher viability than those without the liver cells. This indicates that the liver metabolism has strong effect on the toxicity of the anticancer drug. The results demonstrated that the perfused two chamber cell culture system has the potential to be used as a platform for drug screening in a more physiologically realistic environment.
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Tian, Haijin, Paul Quehl, Joel Hollender, and Joachim Jose. "Surface display of human cytochrome P450 enzymes 3A4, 1A2, 2C9, 2C19 and 2D6 with cytochrome P450 reductase for drug metabolism studies." In 5th International Electronic Conference on Medicinal Chemistry. Basel, Switzerland: MDPI, 2019. http://dx.doi.org/10.3390/ecmc2019-06333.
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Tourlomousis, Filippos, and Robert C. Chang. "Computational Modeling of 3D Printed Tissue-on-a-Chip Microfluidic Devices as Drug Screening Platforms." In ASME 2014 International Mechanical Engineering Congress and Exposition. American Society of Mechanical Engineers, 2014. http://dx.doi.org/10.1115/imece2014-38454.
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Physiological tissue-on-a-chip technology is enabled by adapting microfluidics to create micro scale drug screening platforms that replicate the complex drug transport and reaction processes in the human liver. The ability to incorporate three-dimensional (3d) tissue models using layered fabrication approaches into devices that can be perfused with drugs offer an optimal analog of the in vivo scenario. The dynamic nature of such in vitro metabolism models demands reliable numerical tools to determine the optimum tissue fabrication process, flow, material, and geometric parameters for the most effective metabolic conversion of the perfused drug into the liver microenvironment. Thus, in this modeling-based study, the authors focus on modeling of in vitro 3d microfluidic microanalytical microorgan devices (3MD), where the human liver analog is replicated by 3d cell encapsulated alginate hydrogel based tissue-engineered constructs. These biopolymer constructs are hosted in the chamber of the 3MD device serving as walls of the microfluidic array of channels through which a fluorescent drug substrate is perfused into the microfluidic printed channel walls at a specified volumetric flow rate assuring Stokes flow conditions (Re<<1). Due to the porous nature of the hydrogel walls, a metabolized drug product is collected as an effluent stream at the outlet port. A rigorous modeling approached aimed to capture both the macro and micro scale transport phenomena is presented. Initially, the Stokes Flow Equations (free flow regime) are solved in combination with the Brinkman Equations (porous flow regime) for the laminar velocity profile and wall shear stresses in the whole shear mediated flow regime. These equations are then coupled with the Convection-Diffusion Equation to yield the drug concentration profile by incorporating a reaction term described by the Michael-Menten Kinetics model. This effectively yields a convection-diffusion–cell kinetics model (steady state and transient), where for the prescribed process and material parameters, the drug concentration profile throughout the flow channels can be predicted. A key consideration that is addressed in this paper is the effect of cell mechanotransduction, where shear stresses imposed on the encapsulated cells alter the functional ability of the liver cell enzymes to metabolize the drug. Different cases are presented, where cells are incorporated into the geometric model either as voids that experience wall shear stress (WSS) around their membrane boundaries or as solid materials, with linear elastic properties. As a last step, transient simulations are implemented showing that there exists a tradeoff with respect the drug metabolized effluent product between the shear stresses required and the residence time needed for drug diffusion.