Drug Metabolism and Drug Interactions最新文献

{"title":"Evaluation of partial area under the concentration time curve to estimate midazolam apparent oral clearance for cytochrome P450 3A phenotyping.","authors":"Wei Tai,&nbsp;Sheryl L Gong,&nbsp;Shirley M Tsunoda,&nbsp;Howard E Greenberg,&nbsp;J Christopher Gorski,&nbsp;Scott R Penzak,&nbsp;S Aubrey Stoch,&nbsp;Joseph D Ma","doi":"10.1515/dmdi-2013-0040","DOIUrl":"https://doi.org/10.1515/dmdi-2013-0040","url":null,"abstract":"<p><strong>Background: </strong>Midazolam apparent oral clearance (CLORAL) is used to estimate intestinal and hepatic cytochrome P450 (CYP) 3A activity. A limited sampling approach was performed to access a midazolam partial area under the concentration time curve (AUC) to estimate CLORAL.</p><p><strong>Methods: </strong>Midazolam plasma concentrations from healthy adults were obtained during CYP3A baseline (n=116), inhibition (n=75), and induction or activation (n=66) from seven published studies. Observed CLORAL and partial AUCs of AUC0-2, AUC0-4, AUC0-6, AUC1-2, AUC1-4, AUC2-4, and AUC2-6 were determined by noncompartmental analysis. Subject data were randomly divided into a training set and a validation set. Linear regression equations, derived from partial AUCs, were developed from training set data. Predicted CLORAL was determined from these equations from validation set data. Preset criterion was a coefficient of determination (r2) greater than or equal to 0.9. Bias and precision were evaluated by relative percent mean prediction error (%MPE) and relative percent mean absolute error (%MAE).</p><p><strong>Results: </strong>During CYP3A baseline conditions, all of the evaluated CLORAL equations had unacceptable r2 (range: 0.34-0.86). During CYP3A inhibition, all of the evaluated CLORAL equations had unacceptable %MAE. Acceptable r2, %MPE, and %MAE were observed during CYP3A induction/activation with AUC0-4 (r2=0.99, %MPE=3.9, %MAE=12.5) and AUC1-4 (r2=0.99, %MPE=6%, %MAE=11.1%). The same equations also predicted the extent of CYP3A induction as a lack of equivalence was observed with AUC0-4 and AUC1-4.</p><p><strong>Conclusions: </strong>Midazolam partial AUCs were unable to estimate CYP3A activity during the evaluated baseline and inhibitory conditions. Midazolam CLORAL utilizing a partial AUC0-4 and AUC1-4 was able to estimate CYP3A induction with rifampin and Ginkgo biloba extract.</p>","PeriodicalId":11319,"journal":{"name":"Drug Metabolism and Drug Interactions","volume":"28 4","pages":"217-23"},"PeriodicalIF":0.0,"publicationDate":"2013-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1515/dmdi-2013-0040","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"31798976","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"New challenges for pharmacogenomics.","authors":"Ron H N van Schaik","doi":"10.1515/dmdi-2013-0060","DOIUrl":"https://doi.org/10.1515/dmdi-2013-0060","url":null,"abstract":"","PeriodicalId":11319,"journal":{"name":"Drug Metabolism and Drug Interactions","volume":"28 4","pages":"191-2"},"PeriodicalIF":0.0,"publicationDate":"2013-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1515/dmdi-2013-0060","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"31976457","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CYP3A4/5 combined genotype analysis for predicting statin dose requirement for optimal lipid control.","authors":"Joseph Paul Kitzmiller,&nbsp;Danielle M Sullivan,&nbsp;Mitchell A Phelps,&nbsp;Danxin Wang,&nbsp;Wolfgang Sadee","doi":"10.1515/dmdi-2012-0031","DOIUrl":"https://doi.org/10.1515/dmdi-2012-0031","url":null,"abstract":"<p><strong>Background: </strong>Statins are indicated for prevention of atherosclerotic cardiovascular disease. Metabolism of certain statins involves the cytochrome P450 3A (CYP3A) enzymes, and CYP3A4*22 significantly influences the dose needed for achieving optimal lipid control for atorvastatin, simvastatin, and lovastatin. CYP3A4/5 combined genotype approaches have proved useful in some studies involving CYP3A substrates. We intend to compare a combined genotype analysis to our previously reported single gene CYP3A4 analysis.</p><p><strong>Methods: </strong>A total of 235 patients receiving stable statin doses were genotyped and grouped by CYP3A4/5 status.</p><p><strong>Results: </strong>The number and demographic composition of the patients categorized into the combined genotype groups were consistent with those reported for other cohorts. Dose requirement was significantly associated with the ordered combined-genotype grouping; median daily doses were nearly 40% greater for CYP3A4/5 intermediate metabolizers compared with poor metabolizers, and median daily doses were nearly double for extensive metabolizers compared with poor metabolizers. The combined-genotype approach, however, did not improve the genotype-dosage correlation p-values when compared with the previously-reported analysis; values changed from 0.129 to 0.166, 0.036 to 0.185, and 0.014 to 0.044 for atorvastatin, simvastatin, and the combined statin analysis, respectively.</p><p><strong>Conclusions: </strong>The previously-reported single-gene approach was superior for predicting statin dose requirement in this cohort.</p>","PeriodicalId":11319,"journal":{"name":"Drug Metabolism and Drug Interactions","volume":"28 1","pages":"59-63"},"PeriodicalIF":0.0,"publicationDate":"2013-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1515/dmdi-2012-0031","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"31158090","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Applying systems biology in drug discovery and development.","authors":"Jean-Pierre Galizzi,&nbsp;Brian Paul Lockhart,&nbsp;Antoine Bril","doi":"10.1515/dmdi-2013-0002","DOIUrl":"https://doi.org/10.1515/dmdi-2013-0002","url":null,"abstract":"<p><p>Translational research is a continuum between clinical and basic research where the patient is the center of the research process. It brings clinical research to a starting point for the drug discovery process, permitting the generation of a more robust pathophysiological hypothesis essential for a better selection of drug targets and candidate optimization. It also establishes the basis of early proof for clinical concept studies, preferably in phase I, for which biomarkers and surrogate endpoints can often be used. Systems biology is a prerequisite approach to translational research where technologies and expertise are integrated and articulated to support efficient and productive realization of this concept. The first component of systems biology relies on omics-based technologies and integrates the changes in variables, such as genes, proteins and metabolites, into networks that are responsible for an organism's normal and diseased state. The second component of systems biology is in the domain of computational methods, where simulation and modeling create hypotheses of signaling pathways, transcription networks, physiological processes or even cell- or organism-based models. The simulations aim to show the origin of perturbations of the system that lead to pathological states and what treatment could be achieved to ameliorate or normalize the system. This review discusses how translational research and systems biology together could improve global understanding of drug targets, suggest new targets and approaches for therapeutics, and provide a deeper understanding of drug effects. Taken together, these types of analyses can lead to new therapeutic options while improving the safety and efficacy of new and existing medications.</p>","PeriodicalId":11319,"journal":{"name":"Drug Metabolism and Drug Interactions","volume":"28 2","pages":"67-78"},"PeriodicalIF":0.0,"publicationDate":"2013-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1515/dmdi-2013-0002","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"31379987","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cytochrome P450 genetic polymorphisms of Mexican indigenous populations.","authors":"Martha Sosa-Macías,&nbsp;Adrián Llerena","doi":"10.1515/dmdi-2013-0037","DOIUrl":"https://doi.org/10.1515/dmdi-2013-0037","url":null,"abstract":"<p><p>This review focuses on the genetic polymorphisms of the cytochrome P450 (CYP) genes in Mexican indigenous populations, who are a part of the wide ethnic diversity of this country. These native groups have a particular historical trajectory that is different from the Mexican Mestizos. This variability may be reflected in the frequency distribution of polymorphisms in the CYP genes that encode enzymes involved in the metabolism of drugs and other xenobiotics. Therefore, these polymorphisms may affect drug efficacy and safety in indigenous populations in Mexico. The present study aimed to analyze the prevalence of CYP polymorphisms in indigenous Mexicans and to compare the results with studies in Mexican Mestizos. Because the extrapolation of pharmacogenetic data from Mestizos is not applicable to the majority of indigenous groups, pharmacogenetic studies directed at indigenous populations need to be developed. The Amerindians analyzed in this study showed a low phenotypic (CYP2D6) and genotypic (CYP2D6, CYP2C9) diversity, unlike Mexican Mestizos. The frequency of polymorphisms in the CYP1A1, CYP2C19, CYP2E1, and CYP3A4 genes was more similar among the Amerindians and Mexican Mestizos, with the exception of the CYP1A2 gene, whose *1F variant frequency in Mexican Amerindians was the highest described to date.</p>","PeriodicalId":11319,"journal":{"name":"Drug Metabolism and Drug Interactions","volume":" ","pages":"193-208"},"PeriodicalIF":0.0,"publicationDate":"2013-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1515/dmdi-2013-0037","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40253619","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Quantitative structure-activity relationship analysis of thiazolidineones: potent antidiabetic compounds.","authors":"Vijay Kumar Vishvakarma,&nbsp;Prashant Singh,&nbsp;Monica Dubey,&nbsp;Kamlesh Kumari,&nbsp;Ramesh Chandra,&nbsp;Narender D Pandey","doi":"10.1515/dmdi-2012-0036","DOIUrl":"https://doi.org/10.1515/dmdi-2012-0036","url":null,"abstract":"<p><strong>Background: </strong>Type 2 diabetes is the most common form of diabetes, accounting for over 90% of cases. Current treatment approaches for type 2 diabetes include diet, exercise, and a variety of pharmacologic agents, including insulin, biguanides, sulfonylureas, and thiazolidinediones.</p><p><strong>Methods: </strong>In the present scenario, researchers focused themselves on thiazolidine ring-based compounds to cure type 2 diabetes mellitus. Among the peroxisome proliferator activated receptor (PPAR) family, PPAR-γ is the most effective in curing glucose homeostasis.</p><p><strong>Results and conclusions: </strong>Thiazolidine ring-based compounds act as PPAR-γ agonists, and herein, we have successfully developed nine derivatives of thiazolidine ring-based compounds that are found to be biologically potent using two-dimensional quantitative structure-activity relationship model.</p>","PeriodicalId":11319,"journal":{"name":"Drug Metabolism and Drug Interactions","volume":"28 1","pages":"31-47"},"PeriodicalIF":0.0,"publicationDate":"2013-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1515/dmdi-2012-0036","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"31337378","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mitragyna speciosa Korth leaves extracts induced the CYP450 catalyzed aminopyrine-N-demethylase (APND) and UDP-glucuronosyl transferase (UGT) activities in male Sprague-Dawley rat livers.","authors":"Juzaili Azizi,&nbsp;Sabariah Ismail,&nbsp;Sharif Mahsufi Mansor","doi":"10.1515/dmdi-2012-0039","DOIUrl":"https://doi.org/10.1515/dmdi-2012-0039","url":null,"abstract":"<p><strong>Background: </strong>Mitragyna speciosa leaves have been abused by drug addicts as some of the alkaloids (mainly mitragynine) from the plant possess opiate and cocaine-like effects. These bring to its prohibition in Malaysia in 2004 as consumption of M. speciosa leaves has been perceived to lead to the abuse of other drugs such as cannabis and heroin.</p><p><strong>Methods: </strong>In the current study, the in vitro and in vivo effects of M. speciosa methanolic, aqueous and total alkaloid leaves extracts on drug metabolizing enzymes, namely, cytochrome P450s (CYP450s) and UDP-glucuronosyl transferase (UGT) had been evaluated in rat liver cytosolic fraction and microsomes. Aminopyrine and p-nitrophenol (pNP) were employed as probe substrates in aminopyrine N-demethylase (APND) and UGT enzyme assays, respectively. Furthermore, mitragynine was also tested in vitro for its likelihood to inhibit APND and UGT activity. The assessment of the enzyme activity was conducted using spectrophotometric methods.</p><p><strong>Results: </strong>In vitro, the IC50 value could only be obtained for the methanolic extract in APND study (595.30±30.78 µg/mL) and not in other studies due to the enzyme percentage inhibitions being <70%. In contrast to the in vitro study, the oral treatment of male Sprague-Dawley rats for 14 days with 50, 100 and 200 mg/kg of methanolic and aqueous extracts and with 5, 10 and 20 mg/kg of total alkaloid extract showed a profound increment on the APND and UGT activities.</p><p><strong>Conclusions: </strong>The current findings showed that possibilities exist for herb-drug interaction with increased clearance of drugs, which are primarily metabolized by CYP450s and UGT1A6 among M. speciosa leaves extract users.</p>","PeriodicalId":11319,"journal":{"name":"Drug Metabolism and Drug Interactions","volume":"28 2","pages":"95-105"},"PeriodicalIF":0.0,"publicationDate":"2013-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1515/dmdi-2012-0039","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"31352569","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"An update on the constitutive androstane receptor (CAR).","authors":"Ferdinand Molnár,&nbsp;Jenni Küblbeck,&nbsp;Johanna Jyrkkärinne,&nbsp;Viktória Prantner,&nbsp;Paavo Honkakoski","doi":"10.1515/dmdi-2013-0009","DOIUrl":"https://doi.org/10.1515/dmdi-2013-0009","url":null,"abstract":"<p><p>The constitutive androstane receptor (CAR; NR1I3) has emerged as one of the main drug- and xenobiotic-sensitive transcriptional regulators. It has a major effect on the expression of several oxidative and conjugative enzymes and transporters, and hence, CAR can contribute to drug/drug interactions. Novel functions for CAR are also emerging: it is able to modulate the metabolic fate of glucose, lipids, and bile acids, and it is also involved in cell-cell communication, regulation of the cell cycle, and chemical carcinogenesis. Here, we will review the recent information available on CAR and its target gene expression, its interactions with partner proteins and mechanisms of action, interindividual and species variation, and current advances in CAR ligand selectivity and methods used in interrogation of its ligands.</p>","PeriodicalId":11319,"journal":{"name":"Drug Metabolism and Drug Interactions","volume":"28 2","pages":"79-93"},"PeriodicalIF":0.0,"publicationDate":"2013-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1515/dmdi-2013-0009","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"31476440","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ospemifene metabolism in humans in vitro and in vivo: metabolite identification, quantitation, and CYP assignment of major hydroxylations.","authors":"Ari Tolonen,&nbsp;Pasi Koskimies,&nbsp;Miia Turpeinen,&nbsp;Jouko Uusitalo,&nbsp;Risto Lammintausta,&nbsp;Olavi Pelkonen","doi":"10.1515/dmdi-2013-0016","DOIUrl":"https://doi.org/10.1515/dmdi-2013-0016","url":null,"abstract":"<p><strong>Background: </strong>The metabolism of ospemifene, a novel nonsteroidal selective estrogen receptor modulator, was investigated as part of its development.</p><p><strong>Methods: </strong>Metabolite identification, tentative quantitation, and CYP assignment of ospemifene were performed in human liver microsomes or homogenate incubations and in plasma samples from volunteer humans. The potential contributions of CYP enzymes were determined by recombinant human CYPs. Metabolite identification and tentative quantification were performed by liquid chromatography-mass spectrometry.</p><p><strong>Results: </strong>The relative abundances of metabolites produced were dependent on ospemifene concentration and liver preparation, but the largest quantities of 4- and 4'-hydroxy-ospemifene (and their glucuronides in smaller quantities) were produced in human liver microsomes at low ospemifene concentrations. Other metabolites were detected in in vitro incubation with human liver including a direct glucuronide of ospemifene and some metabolites with only minor abundance. In human plasma samples, 4-hydroxy-ospemifene was the most abundant metabolite, representing about 25% of the abundance of the parent compound. All the other metabolites detected in plasma, including 4'-hydroxy-ospemifene, represented <7% of the abundance of ospemifene. Several CYP enzymes participated in 4-hydroxylation, including CYP2C9, CYP2C19, CYP2B6, and CYP3A4, whereas CYP3A enzymes were the only ones to catalyze 4'-hydroxylation.</p><p><strong>Conclusions: </strong>In vitro incubations with liver preparations provided a rather reliable starting point in the search for potential metabolites in clinical settings. The in vitro metabolite profile is informative for the in vivo metabolite profile, especially regarding the major hydroxylated metabolites. However, it is anticipated that extended in vivo exposures may result in an increased production of more distal metabolites from major metabolites.</p>","PeriodicalId":11319,"journal":{"name":"Drug Metabolism and Drug Interactions","volume":"28 3","pages":"153-61"},"PeriodicalIF":0.0,"publicationDate":"2013-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1515/dmdi-2013-0016","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"31476441","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Utility of a column-switching LC/MS/MS method in cytochrome P450 inhibition assays using human liver microsomes.","authors":"Dayanidhi Behera,&nbsp;Rambabu Pattem,&nbsp;M Siva Selva Kumar,&nbsp;Girish S Gudi","doi":"10.1515/dmdi-2013-0004","DOIUrl":"https://doi.org/10.1515/dmdi-2013-0004","url":null,"abstract":"<p><strong>Background: </strong>Liquid chromatography-tandem mass spectrometry (LC/MS/MS)-based in vitro cytochrome P450 (CYP) inhibition assays in pooled human liver microsomes using therapeutically relevant probe drugs are recommended by the US Food and Drug Administration to assess the potential for drug-drug interactions. As these assays are used routinely in pharmaceutical drug discovery screening of new chemical entities for drug interaction liabilities, there is a need to have higher analytical throughput. Column-switching methods may offer increased chromatographic throughput while maintaining the quality of data generated.</p><p><strong>Methods: </strong>In this study, the CYP3A4 inhibition assay was used as a potential application to demonstrate the performance of a dual-column parallel chromatographic system in a column-switching mode. Testosterone 6β-hydroxylation was monitored and IC50 values of known CYP3A4 inhibitors were determined using conventional as well as column-switching LC/MS/MS methods.</p><p><strong>Results: </strong>Mean IC50 values of ketoconazole, itraconazole and verapamil were 0.056, 0.061 and 23 μM (conventional method) compared to 0.05, 0.057 and 26 μM (column-switching method), respectively. The two different chromatographic methods resulted in IC50 values that were not statistically different and were within a twofold range, demonstrating reproducibility of results. Further, the column-switching method saved nearly 50% of analytical time in comparison to the conventional chromatographic method, indicating increased throughput leading to better utilization of mass spectrometer time without compromising the quality of data.</p><p><strong>Conclusions: </strong>Similar column-switching methods may be used for other isoforms as well and offer a convenient increased analytical throughput in CYP inhibition assays.</p>","PeriodicalId":11319,"journal":{"name":"Drug Metabolism and Drug Interactions","volume":"28 3","pages":"177-85"},"PeriodicalIF":0.0,"publicationDate":"2013-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1515/dmdi-2013-0004","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"31476442","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}