Dissertations / Theses on the topic 'Human liver microsomes'
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Emery, Maurice George. "Aspects of human CYP 2E1 regulation in health and disease /." Thesis, Connect to this title online; UW restricted, 1999. http://hdl.handle.net/1773/7943.
Full textMcLure, James Alexander, and james mclure@flinders edu au. "Physicochemical determinants of the non-specific binding of drugs to human liver microsomes." Flinders University. Medicine, 2008. http://catalogue.flinders.edu.au./local/adt/public/adt-SFU20081102.165952.
Full textSchjølberg, Tiril Helgesen. "In Vitro Synthesis of Metabolites of three Anabolic Androgenic Steroids, by Human Liver Microsomes." Thesis, Norges teknisk-naturvitenskapelige universitet, Institutt for bioteknologi, 2013. http://urn.kb.se/resolve?urn=urn:nbn:no:ntnu:diva-22910.
Full textMaley, Mary. "The role of individual forms of cytochrome P450 in drug metabolism in human liver microsomes." Thesis, University of Aberdeen, 1996. http://digitool.abdn.ac.uk/R?func=search-advanced-go&find_code1=WSN&request1=AAIU078654.
Full textAbu-Omar, Ghada M. "Drug interactions and metabolism of cyclosporin A and steroids by human liver microsomes in vitro." Thesis, University of Aberdeen, 1992. http://digitool.abdn.ac.uk/R?func=search-advanced-go&find_code1=WSN&request1=AAIU545502.
Full textDowsley, Taylor Forbes. "CYP2E1-dependent bioactivation of 1,1-dichloroethylene to reactive intermediates in murine and human lung and liver microsomes." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1999. http://www.collectionscanada.ca/obj/s4/f2/dsk2/ftp02/NQ38304.pdf.
Full textStrömqvist, Malin. "Development of quantitative methods for the determination of vemurafenib and its metabolites in human plasma." Thesis, Linköpings universitet, Kemi, 2014. http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-110076.
Full textShepard, Dale Randall. "The Metabolism of Phenytoin by Human Liver Microsomes and Cytochrome P450s Expressed in Saccharomyces Cerevisiae and COS-1 Cells /." The Ohio State University, 1995. http://rave.ohiolink.edu/etdc/view?acc_num=osu1487931512618872.
Full textUwimana, Eric. "Probing the PCB metabolome: metabolism of chiral and non-chiral polychlorinated biphenyls to chiral hydroxylated metabolites in humans and rats." Diss., University of Iowa, 2018. https://ir.uiowa.edu/etd/6657.
Full textLarabi, Islam Amine. "Nouveaux produits de synthèse : analyse, consommation et métabolisme ; Applications cliniques et médicolégales Rapid and simultaneous screening of new psychoactive substances and conventional drugs of abuse. A comparative study of Biochip Array Technology versus LC-MS/MS in whole blood and urine Development of a sensitive untargeted liquid chromatography– high resolution mass spectrometry screening devoted to hair analysis through a shared MS2 spectra database: A step toward early detection of new psychoactive substances Validation of an UPLC-MS/MS method for the determination of sixteen synthetic cannabinoids in human hair. Application to document chronic use of JWH-122 following a non-fatal overdose Development and validation of liquid chromatography-tandem mass spectrometry targeted screening of 16 fentanyl analogs and U-47700 in hair: Application to 137 authentic samples Prevalence and Surveillance of Synthetic Cathinones Use by Hair Analysis: An Update Review Prevalence of New Psychoactive Substances(NPS) and conventional drugs of abuse (DOA) in high risk populations from Paris(France) and its suburbs A cross sectional study by hair testing(2012–2017) Evaluation of drug abuse by hair analysis and self-reported use among MSM under PrEP: Results from a sub-study of the ANRS-IPERGAY trial. Hair testing for 3‑fluorofentanyl, furanylfentanyl, methoxyacetylfentanyl, carfentanil, acetylfentanyl and fentanyl by LC–MS/MS after unintentional overdose Drug‐facilitated sexual assault (DFSA) involving 4‐methylethcathinone (4‐MEC),3,4‐Methylenedioxypyrovalerone (MDPV), and doxylamine highlighted by hair analysis Metabolic Profiling of Deschloro-N-ethyl-ketamine (O-PCE) and identification of new target metabolites in urine and hair using human liver microsomes and high-resolution accurate mass spectrometry." Thesis, université Paris-Saclay, 2020. http://www.theses.fr/2020UPASL029.
Full textThe aim of the present work was to develop two analytical approaches dedicated to the analysis of new psychoactive substances in different biological matrices (blood, urine and hair). The first approach is based on untargeted screening by both biochip array technology chemiluminescence assay and liquid chromatography coupled to high resolution mass spectrometry (LC-HRMS) and the second corresponds to a targeted screening by liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS). These two approaches were then applied in observational studies to assess the consumption of NPS in high risk populations (overdose, drug abuse, drug facilitated crimes) in clinical and forensic settings. The last part of the work was devoted to the development of a new analytical tool for LC-HRMS data processing which made it possible to study the metabolism of 9 NPS In vitro on human liver microsomes (HLM) and In vivo in biological samples from drug users. This approach has enabled the creation of HRMS spectral library containing 228 metabolites, some of which have been proposed as relevant markers of NPS exposure.This work has resulted on 10 scientific publications and allowed to initiate many multidisciplinary collaborations
Kroetz, Deanna L. "Inhibition of human liver microsomal epoxide hydrolase /." Thesis, Connect to this title online; UW restricted, 1990. http://hdl.handle.net/1773/7958.
Full textVollmar, Christian Verfasser], and Hans H. [Akademischer Betreuer] [Maurer. "New cathinone-derived designer drugs 3-bromomethcathinone and 3-fluoromethcathinone : studies on their metabolism in rat urine and human liver microsomes using GC-MS and LC-high-resolution MS and their detectability in urine / Christian Vollmar. Betreuer: Hans H. Maurer." Saarbrücken : Saarländische Universitäts- und Landesbibliothek, 2014. http://d-nb.info/1053725442/34.
Full textHabenschus, 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/.
Full text(-)-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.
Ameline, Alice. "Aspects analytiques, cliniques et médico-judiciaires des nouvelles substances psychoactives." Thesis, Strasbourg, 2019. http://www.theses.fr/2019STRAJ018/document.
Full textDue to the uncontrolled spread on the Internet and their legal alternative to usual drugs, the new psychoactive substances (NPS), recently appeared (2008), are at the center of recent phenomena of addiction and badly explained deaths. Beyond different challenges in our societies (prevention, legislation), the ability to identify NPS in biological samples, in order to characterize their use, presents many analytical challenges. The main objective of this thesis was to collect biological samples (blood, urine, hair) from cases of exposure to NPS and to characterize the substances present using original analytical methods, in order to enlarge the libraries of mass spectra and improve, as a result, the detection of NPS consumption. In particular, it was intended to increase the detection sensitivity of NPS intake by focusing on the metabolites that are often the major products of elimination. This analytical development, by ultra-high liquid chromatography coupled with tandem mass spectrometry (UHPLC-MS/MS), required several months of optimization in order to obtain a robust, exhaustive and sensitive method. At present, the mass spectra database has 114 NPS and is regularly updated. Thereafter, ma thesis focused on the study of cases of intoxication observed in the emergency department of Strasbourg, but also in legal medicine with situations of deaths and identification of unknown products collected from seizures (powders and crystals). It has also been necessary to implement complementary analytical tools, such as the characterization of metabolites by human liver microsomes (HLMs), and the use of nuclear magnetic resonance (NMR) spectroscopy to accurately identify the compounds and establish their purity degrees. The analytical tools developed, and the strategy adopted, allowed the writing of 18 publications, as well as the setting up of numerous collaborations
Al, Ali Ahmad. "Le dosage des cytochromes P450 (CYPs) humains par spectrométrie de masse : applications en toxicologie." Thesis, Paris 5, 2014. http://www.theses.fr/2014PA05P603/document.
Full textCytochromes P450 (CYPs) play a key role in the oxidative metabolism of many endogenous and exogenous compounds. The expression of CYPs is extremely variable depending on patho-physiological, genetic and environmental factors. The metabolism of xenobiotics by CYPs depends on the nature the quantity and the activity of CYP isoforms involved. Quantitative analysis of CYP expression in organs such as liver, are of particular importance since the biotransformation performed by CYPs is often a critical factor that affects the efficiency, availability and drug toxicity in humans. The most common technique is the immune-quantitation (Western Blot). This technique is limited by the availability and specificity of the antibody. Mass spectrometry-based proteomics, able to analyze very small amounts of protein in a mixture, are the methods of choice for identification and quantification of CYPs in different organs. We developed and validated a method for dosing 6 CYPs (1A2, 2C9, 2D6, 2J2, 3A4 and 3A5) by liquid chromatography coupled with mass spectrometry. This simple, rapid, low-cost method has an adequate sensitivity, and has been validated in different types of biological matrices (liver and neuronal cell lines, baculosomes). It has been applied at large-scale to analyze these 6 CYPs in 50 human livers samples (microsomes and mitochondria) to study the phenotype/genotype relationship. This method, which could easily be applied to other CYPs, provides an important tool to improve the understanding and prediction of pharmacokinetics and toxicity profile of drugs and other chemicals
Tsai, I.-Lin, and 蔡易霖. "Identify the metabolites of methylone and ethylone using human liver microsomes and human urine." Thesis, 2019. http://ndltd.ncl.edu.tw/handle/8b6k2p.
Full text國立臺灣大學
法醫學研究所
107
Synthetic cathinone is the most frequently abused new psychoactive substances (NPS) in Taiwan. Methylone and ethylone, which were categorized as scheduled III drug in 2012 and 2016 in Taiwan, are two derivatives of synthetic cathinone. It is important to investigate the metabolism of methylone and ethylone in order to find specific markers in human specimen. However, the metabolic profile of these two compounds are still limited especially for phase II metabolites. In previous study, methylone and ethylone each formed 7 metabolites through 5 metabolic pathways. In this study, we in vitro synthesized phase I and phase II metabolites by human liver microsomes and cytosols, and observed metabolites by fragment pattern and accurate mass using liquid chromatography-mass spectrometry (LC-MS) and liquid chromatography-high resolution mass spectrometry (LC-HRMS). Total eight phase I metabolites and three phase II metabolites were detected. Three in vitro phase II metabolites, sulfate conjugate of dihydroxymethcathinone (DHMC-S) from methylone, sulfate conjugate of dihydroxyethcathinone (DHEC-S) from ethylone and glucuronide conjugate of dihydroxymethcathinone (DHEC-G) from ethylone have never reported before. The method was established to identify the metabolites in human specimens. Urine samples from methylone and ethylone abusers were analyzed to evaluate the composition of metabolites. Dihydromethylone and glucuronide conjugate of 3-hydroxy-4-methoxymeth-cathinone (3-OH-4-MeO-MC-G) or its isomer 4-OH-3-MeO-MC-G were major metabolites of methylone, and Dihydroethylone and DHEC-S were major metabolites of ethylone in abusers urine samples. But more urine sample should be analyzed to make the metabolic trend more obvious.
McLure, James Alexander. "Physicochemical determinants of the non-specific binding of drugs to human liver microsomes." 2008. http://catalogue.flinders.edu.au/local/adt/public/adt-SFU20081102.165952/index.html.
Full textMadeira, Maria. "The effect of cimetidine on dextromethorphan O-demethylase activity of human liver microsomes and recombinant CYP2D6." Thesis, 2003. http://hdl.handle.net/2429/14177.
Full textRiley, Anna Ruth. "Propoxyphene, Norpropoxyphene, and Proadifen (SKF-525A) Are Mechanism Based Inhibitors of CYP3A4, CYP3A5, and CYP3A in Human Liver Microsomes." Thesis, 2008. http://hdl.handle.net/1805/1855.
Full textThe purpose of this study is to determine if propoxyphene and norpropoxyphene are mechanism-based (irreversible) inhibitors of CYP3A, and to determine if propoxyphene and norpropoxyphene are reversible inhibitors of CYP3A. Mechanismbased inhibition is a type of irreversible inhibition that results from an inhibitor or its metabolite binding to an enzyme during drug metabolism, which renders the enzyme nonfunctional. Propoxyphene is an analgesic that is frequently prescribed in the United States and Europe. It is metabolized by CYP3A enzymes, and is an irreversible inhibitor of CYP3A4. The major metabolite of propoxyphene is norpropoxyphene, which has not been extensively studied for enzyme inhibition. Proadifen (SKF-525a) is not a marketed drug, but it is a known CYP inhibitor that is structurally similar to propoxyphene and norpropoxyphene. Propoxyphene, norpropoxyphene, and proadifen were characterized in these studies with CYP3A4(+b5), CYP3A5(+b5) and pooled human liver microsomes. Time-dependent and concentration-dependent loss of activity of CYP3A was measured by formation of testosterone product. Propoxyphene and norpropoxyphene exhibited the greatest inhibition with CYP3A in human liver microsomes, followed by CYP3A4(+b5), and CYP3A5(+b5). Both compounds formed metabolic-inhibitor complexes with vi CYP3A4(+b5) and CYP3A5(+b5), but not with human liver microsomes. Proadifen was a more potent inhibitor of CYP3A4(+b5) than of human liver microsomes and CYP3A5(+b5). The KI values of propoxyphene and CYP3A4(+b5) and human liver microsomes fall within the range of reported therapeutic blood levels of propoxyphene, with reversible inhibition constants (Ki values) above therapeutic blood concentrations for propoxyphene and norpropoxyphene. The KI values of norpropoxyphene and CYP3A4(+b5) and human liver microsomes are higher than most reported blood levels, except for blood levels after repeated dosing of propoxyphene at high concentrations. The predicted change in the area under the plasma concentration versus time curve of an orally administered CYP3A substrate with propoxyphene (AUC'po/AUCpo) was calculated for common CYP3A substrates. The AUC'po/AUCpo ratios are four to twenty-five times higher with co-administration of propoxyphene based on in vitro kinetic parameters. Propoxyphene and norpropoxyphene may cause adverse events when chronically administered at high doses and/or when co-administered with other CYP3A substrates.
Hsun-Yi, Tseng, and 曾薰儀. "Study on Metabolism of Territrem A by Human Liver Microsomes and Human Cytochrome P450 3A4 expressed in V79 Chinese Hamster cells." Thesis, 2000. http://ndltd.ncl.edu.tw/handle/81149866620663181463.
Full text國立臺灣大學
毒理學研究所
88
Abstract Territrem A (TRA) is a tremogenic mycotoxin isolated from the chloroform extracts of the sub-merged rice culture of Aspergillus terreus 23-1. The previous studies indicated that three metabolites, designated as MA1, MAX and MA2, were obtained when TRA was the substrate in liver microsomes of adult male Wistar rats which was pretreated with phenobarbital or dexamethasone. However, only MA1 was formed from TRA in liver microsomes of female rats. From chemical and immuno inhibition studies, we had suggested that CYP3A1/2 mainly involved in TRA metabolism. In the present study, I investigate the territrem A metabolism in human liver microsomes and in V79 Chinese Hamster cells, designed as V79MZh3A4, in which human cytochrome P450 3A4 were expressed. The aims of this study were to elucidate the questions as following: (1) TRA metabolism in different species. (2) TRA metabolism in sex difference of human. (3) Role of CYP3A4 in TRA metabolism. From the studies, I have obtained the following results. (1) Both human livers and V79MZh3A4 cells could express the activities of testosterone 6hydroxylase. Otherwise, the testosterone 6hydroxylase was not being determined in V79MZ cells. (2) Inmmunobloting assay showed that CYP3A4 protein was detected in human liver microsomes and V79MZh3A4 cells, but not in V79MZ cells. (3) When TRA was used as the substrate, MA1 and trace amount MAX were formed in male and female human liver microsomes. (4) Furthermore the results obtained was using live V79MZh3A4 cells showed only MA1 was found. When MA1 was used as the substrate in the same experimental condition, no metabolites were found. (5) In enzyme kinetics study, I found that V79MZh3A4 cells could metabolize TRA judged from the value of Vmax / Km of MA1 calculatedly activity. (6) The specific cytochrome P450 inhibitor of CYP3A4, such as ketoconazole, inhibited the activities of testosterone 6 - hydroxylase as well as MA1 in human liver microsomes was increased of dose of inhibition. Therefore, it is suggested that CYP3A4 has a major role in metabolic pathway from TRA to MA 1.
Liu, X., L. Hu, G. Ge, B. Yang, J. Ning, S. Sun, L. Yang, Klaus Pors, and J. Gu. "Quantitative analysis of cytochrome P450 isoforms in human liver microsomes by the combination of proteomics and chemical probe-based assay." 2014. http://hdl.handle.net/10454/10502.
Full textCytochrome P450 (CYP) is one of the most important drug-metabolizing enzyme families, which participates in the biotransformation of many endogenous and exogenous compounds. Quantitative analysis of CYP expression levels is important when studying the efficacy of new drug molecules and assessing drug-drug interactions in drug development. At present, chemical probe-based assay is the most widely used approach for the evaluation of CYP activity although there are cross-reactions between the isoforms with high sequence homologies. Therefore, quantification of each isozyme is highly desired in regard to meeting the ever-increasing requirements for carrying out pharmacokinetics and personalized medicine in the academic, pharmaceutical, and clinical setting. Herein, an absolute quantification method was employed for the analysis of the seven isoforms CYP1A2, 2B6, 3A4, 3A5, 2C9, 2C19, and 2E1 using a proteome-derived approach in combination with stable isotope dilution assay. The average absolute amount measured from twelve human liver microsomes samples were 39.3, 4.3, 54.0, 4.6, 10.3, 3.0, and 9.3 (pmol/mg protein) for 1A2, 2B6, 3A4, 3A5, 2C9, 2C19, and 2E1, respectively. Importantly, the expression level of CYP3A4 showed high correlation (r = 0.943, p < 0.0001) with the functional activity, which was measured using bufalin-a highly selective chemical probe we have developed. The combination of MRM identification and analysis of the functional activity, as in the case of CYP3A4, provides a protocol which can be extended to other functional enzyme studies with wide application in pharmaceutical research.
Numa, Andres Masato. "The effect of Ginkgo Biloba extract on valproic acid metabolism by human liver microsomes from donors with the CYP2C9*1/*1 genotype." Thesis, 2005. http://hdl.handle.net/2429/17242.
Full textPharmaceutical Sciences, Faculty of
Graduate
Li, Yibai. "Pharmacogenetics of ketamine metabolism and immunopharmacology of ketamine." Thesis, 2014. http://hdl.handle.net/2440/106345.
Full textThesis (Ph.D.) (Research by Publication) -- University of Adelaide, School of Medical Sciences, 2014.
Seibert, C., B. R. Davidson, B. J. Fuller, Laurence H. Patterson, W. J. Griffiths, and Y. Wang. "Multiple-approaches to the identification and quantification of cytochromes P450 in human liver tissue by mass spectrometry." 2009. http://hdl.handle.net/10454/6179.
Full textSutherland, Mark H., Jason H. Gill, Paul M. Loadman, Jonathan P. Laye, Helen M. Sheldrake, Nicola A. Illingworth, Mohammed N. Alandas, et al. "Antitumor activity of a duocarmycin analogue rationalized to be metabolically activated by cytochrome P450 1A1 in human transitional cell carcinoma of the bladder." 2012. http://hdl.handle.net/10454/6210.
Full textWe identify cytochrome P450 1A1 (CYP1A1) as a target for tumor-selective drug development in bladder cancer and describe the characterization of ICT2700, designed to be metabolized from a prodrug to a potent cytotoxin selectively by CYP1A1. Elevated CYP1A1 expression was shown in human bladder cancer relative to normal human tissues. RT112 bladder cancer cells, endogenously expressing CYP1A1, were selectively chemosensitive to ICT2700, whereas EJ138 bladder cells that do not express CYP1A1 were significantly less responsive. Introduction of CYP1A1 into EJ138 cells resulted in 75-fold increased chemosensitivity to ICT2700 relative to wild-type EJ138. Negligible chemosensitivity was observed in ICT2700 in EJ138 cells expressing CYP1A2 or with exposure of EJ138 cells to CYP1B1- or CYP3A4-generated metabolites of ICT2700. Chemosensitivity to ICT2700 was also negated in EJ138-CYP1A1 cells by the CYP1 inhibitor alpha-naphthoflavone. Furthermore, ICT2700 did not induce expression of the AhR-regulated CYP1 family, indicating that constitutive CYP1A1 expression is sufficient for activation of ICT2700. Consistent with the selective activity by CYP1A1 was a time and concentration-dependent increase in gamma-H2AX protein expression, indicative of DNA damage, associated with the activation of ICT2700 in RT112 but not EJ138 cells. In mice-bearing CYP1A1-positive and negative isogenic tumors, ICT2700 administration resulted in an antitumor response only in the CYP1A1-expressing tumor model. This antitumor response was associated with detection of the CYP1A1-activated metabolite in tumors but not in the liver. Our findings support the further development of ICT2700 as a tumor-selective treatment for human bladder cancers.