Drug Metabolism and Pharmacokinetics最新文献_第2页

Evaluation of OATP1B inhibitory potential using an endogenous biomarker coproporphyrin-I in new drug applications: Case reports submitted by 2024 内源性生物标志物coproporphyrin-I在新药应用中的抑制潜力评估：2024年提交的病例报告。

IF 2.2 4区医学

Drug Metabolism and Pharmacokinetics Pub Date : 2026-02-01 Epub Date: 2025-12-17 DOI: 10.1016/j.dmpk.2025.101513

Ryosuke Watari

{"title":"Evaluation of OATP1B inhibitory potential using an endogenous biomarker coproporphyrin-I in new drug applications: Case reports submitted by 2024","authors":"Ryosuke Watari","doi":"10.1016/j.dmpk.2025.101513","DOIUrl":"10.1016/j.dmpk.2025.101513","url":null,"abstract":"<div><div>Coproporphyrin-I (CP-I), an endogenous biomarker for organic anion transporting polypeptide (OATP) 1B, is a critical tool for evaluating the inhibitory potential of OATP1B in humans. The final International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) M12 guideline (Step 4) recognizes CP-I as a validated biomarker for this purpose. In addition, the area under the concentration–time curve (AUC) ratio and the maximum concentration (C<sub>max</sub>) ratio of CP-I have been used as indices to assess OATP1B inhibition, with the cutoff value set at 1.25. Because ICH M12 now describes the application of CP-I as a biomarker for evaluating the inhibitory potential of OATP1B, CP-I data are expected to be increasingly used in future new drug applications (NDAs). This review presents case studies of NDAs submitted by 2024 that incorporated CP-I to evaluate the OATP1B inhibitory potential of new molecular entities before the finalization of ICH M12 Step 4. In addition, considerations and perspectives regarding the evaluation of OATP1B inhibition using CP-I are discussed. These examples can serve as references for future applications using CP-I and the regulatory acceptance of other endogenous biomarkers, such as N<sup>1</sup>-methylnicotinamide and pyridoxic acid, as described in the ICH M12 guideline.</div></div>","PeriodicalId":11298,"journal":{"name":"Drug Metabolism and Pharmacokinetics","volume":"66 ","pages":"Article 101513"},"PeriodicalIF":2.2,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145916681","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Role of metabolites in drug-drug interactions 代谢物在药物-药物相互作用中的作用。

IF 2.2 4区医学

Drug Metabolism and Pharmacokinetics Pub Date : 2026-02-01 Epub Date: 2025-12-08 DOI: 10.1016/j.dmpk.2025.101511

Nina Isoherranen

{"title":"Role of metabolites in drug-drug interactions","authors":"Nina Isoherranen","doi":"10.1016/j.dmpk.2025.101511","DOIUrl":"10.1016/j.dmpk.2025.101511","url":null,"abstract":"<div><div>Since the publication of the metabolites in safety testing (MIST) guidance by the US FDA in 2009, there has been continuous interest and expansion in research aimed at predicting and characterizing circulating metabolites. Several systematic reviews and original research articles have been published to assess the role of metabolites in drug-drug interactions. Abundant circulating metabolites have been found to be common with classic cytochrome P450 (CYP) enzyme inhibitors and with new drugs in development. This has raised the need for better tools to predict significant circulating metabolites from preclinical data to streamline metabolite testing. This review summarizes the current recommendations for metabolite testing, evaluates the existing data on reversible and time-dependent inhibition of CYP enzymes by circulating metabolites, and explores the potential inhibition of drug transporters by circulating metabolites. The possible role of metabolites in induction of CYP enzymes is also discussed. The mathematical methods to incorporate multiple precipitants into risk assessment and quantitative prediction methods for inhibition and induction are summarized. Finally, the unique considerations regarding PBPK modeling of metabolites are discussed to highlight potential differences in the metabolite liver concentrations used in static versus more dynamic PBPK prediction methods.</div></div>","PeriodicalId":11298,"journal":{"name":"Drug Metabolism and Pharmacokinetics","volume":"66 ","pages":"Article 101511"},"PeriodicalIF":2.2,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145911050","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The rational use of PBPK to assess the changing DDI liability in pediatrics: Model qualification and the move towards best practice 合理使用PBPK评估儿科不断变化的DDI责任：模型资格和走向最佳实践。

IF 2.2 4区医学

Drug Metabolism and Pharmacokinetics Pub Date : 2026-02-01 Epub Date: 2025-11-26 DOI: 10.1016/j.dmpk.2025.101509

Trevor N. Johnson , Jean Dinh , Roz Southall , Amin Rostami-Hodjegan

{"title":"The rational use of PBPK to assess the changing DDI liability in pediatrics: Model qualification and the move towards best practice","authors":"Trevor N. Johnson , Jean Dinh , Roz Southall , Amin Rostami-Hodjegan","doi":"10.1016/j.dmpk.2025.101509","DOIUrl":"10.1016/j.dmpk.2025.101509","url":null,"abstract":"<div><div>Many drug-drug interactions (DDIs) in the pediatric population are managed based on data generated in adults, however this is done with little clinical evidence and the assumption of DDIs being similar between adults and pediatric may not be correct. Physiologically Based Pharmacokinetic models have been used extensively to predict DDIs in adults and this evidence is now being accepted by regulators worldwide and in certain cases information from PBPK is feeding directly into the drug labels. Because pediatric PBPK models account for age related changes in physiology and biochemistry they are ideally placed to extrapolate DDI liability from adults to children. However, marrying together all relevant system factors such as ontogeny of enzymes and hepatic blood flow with drug related factors e.g. extraction ratio and fraction unbound is important and is an active area of research. This review will highlight the need for dynamic rather than static PBPK pediatric DDI predictions with a view to recommending the best practice approach.</div></div>","PeriodicalId":11298,"journal":{"name":"Drug Metabolism and Pharmacokinetics","volume":"66 ","pages":"Article 101509"},"PeriodicalIF":2.2,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145916748","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Future directions in drug-drug interaction evaluations: Industry perspective on the ICH M12 guidance 药物相互作用评价的未来方向：ICH M12指南的行业观点。

IF 2.2 4区医学

Drug Metabolism and Pharmacokinetics Pub Date : 2026-02-01 Epub Date: 2025-12-12 DOI: 10.1016/j.dmpk.2025.101512

Kenichi Umehara , Andrew Harrell , Chandra Prakash , Constanze Hilgendorf , T. Eric Ballard , Felix Huth , Justine Badée , Licong Jiang , Manoli Vourvahis , Natasa Pajkovic , Neil Parrott , Nilay Thakkar , Patrik Marroum , Ronald Laethem , Shiyao Xu , Yuan Chen

{"title":"Future directions in drug-drug interaction evaluations: Industry perspective on the ICH M12 guidance","authors":"Kenichi Umehara , Andrew Harrell , Chandra Prakash , Constanze Hilgendorf , T. Eric Ballard , Felix Huth , Justine Badée , Licong Jiang , Manoli Vourvahis , Natasa Pajkovic , Neil Parrott , Nilay Thakkar , Patrik Marroum , Ronald Laethem , Shiyao Xu , Yuan Chen","doi":"10.1016/j.dmpk.2025.101512","DOIUrl":"10.1016/j.dmpk.2025.101512","url":null,"abstract":"<div><div>The ICH M12 Guidance, adopted by the International Council for Harmonisation in 2024, provides a global framework for assessing drug-drug interaction (DDI) risks mediated by metabolic enzymes and drug transporters. The DDI Discussion Group in the International Consortium for Innovation and Quality identifies key challenges in the guidance. In vitro challenges include accounting for protein binding, mitigating overestimations of DDI risks, and interpreting weak enzyme inhibition or induction effects. A case study explores cytochrome P450 (CYP) induction risks by major metabolites. The complexities of UDP-glucuronosyltransferase (UGT) and transporter inhibition or induction are contextualized. Clearance pathway evaluations for low turnover compounds and UGT or transporter substrates are also summarized for object DDIs. Clinically, challenges include the need for validated endogenous biomarkers to improve DDI risk assessments and finding alternatives to rifampin for CYP induction and Organic Anion Transporting polypeptide 1B (OATP1B) inhibition due to nitrosamine: reduced and non-selective induction by drugs like carbamazepine and phenytoin or non-selective OATP inhibition by cyclosporine. Further complexities involve therapeutic-protein DDIs, transporter-enzyme interplay and compounds acting as simultaneous inducers and time-dependent inhibitors. Addressing these gaps requires collaborative efforts to refine predictive models to improve in vitro-in vivo correlations, and to enhance drug development and patient safety.</div></div>","PeriodicalId":11298,"journal":{"name":"Drug Metabolism and Pharmacokinetics","volume":"66 ","pages":"Article 101512"},"PeriodicalIF":2.2,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145911074","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Tyrosine kinase inhibitors, nilotinib and radotinib, suppress both catalytic function and mRNA expression of human cytochrome P450 2J2 and 2C8 酪氨酸激酶抑制剂尼罗替尼和拉多替尼抑制人细胞色素P450 2J2和2C8的催化功能和mRNA表达

IF 2.2 4区医学

Drug Metabolism and Pharmacokinetics Pub Date : 2025-12-01 Epub Date: 2025-08-29 DOI: 10.1016/j.dmpk.2025.101501

Ayaka Kojima , Masayuki Nadai , Hiroshi Yamazaki , Miki Katoh

{"title":"Tyrosine kinase inhibitors, nilotinib and radotinib, suppress both catalytic function and mRNA expression of human cytochrome P450 2J2 and 2C8","authors":"Ayaka Kojima , Masayuki Nadai , Hiroshi Yamazaki , Miki Katoh","doi":"10.1016/j.dmpk.2025.101501","DOIUrl":"10.1016/j.dmpk.2025.101501","url":null,"abstract":"<div><div>Cytochrome P450 (P450 or CYP) 2J2, which metabolizes exogenous medicines and endogenous arachidonic acid to 14,15-epoxyeicosatrienoic acid (14,15-EET), is expressed in various organs and cancer cells. Additionally, CYP2C8 catalyzes the synthesis of 14,15-EET, a vasodilator that promotes cancer cell proliferation. However, the effect of tyrosine kinase inhibitors (TKIs) used in leukemia treatment on CYP2J2 and CYP2C8 remains unclear. This study investigated the effects of 16 TKIs used for leukemia treatment on recombinant CYP2J2-and CYP2C8-mediated processes. Among the TKIs, nilotinib and radotinib strongly inhibited CYP2J2-dependent astemizole <em>O</em>-demethylation and rivaroxaban hydroxylation, and CYP2C8-mediated paclitaxel 6α-hydroxylation (<20 %), with competitive inhibition constants of 0.41 and 0.22 μM, respectively (for astemizole <em>O</em>-demethylation). Nilotinib and radotinib suppressed CYP2J2-and CYP2C8-catalyzed arachidonic acid epoxidation and decreased their mRNA expression in Huh-7 cells (possibly via the peroxisome proliferator-activated receptor α pathway). Given that their inhibition constants are lower than their reported plasma concentrations, both may substantially suppress CYP2J2 and CYP2C8 functional enzyme levels and enzymatic activities in clinical settings. This suppression could potentially alter vasodilation by affecting 14,15-EET production, influencing CYP2J2 and CYP2C8-mediated drug-disease (conditions) and drug-drug interactions.</div></div>","PeriodicalId":11298,"journal":{"name":"Drug Metabolism and Pharmacokinetics","volume":"65 ","pages":"Article 101501"},"PeriodicalIF":2.2,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145183717","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Metabolism of simvastatin by Streptomyces griseolus CYP105A1 and its variants for the production of human simvastatin metabolites 灰色链霉菌CYP105A1及其变异对辛伐他汀的代谢及其对人类辛伐他汀代谢物的产生

IF 2.2 4区医学

Drug Metabolism and Pharmacokinetics Pub Date : 2025-12-01 Epub Date: 2025-10-24 DOI: 10.1016/j.dmpk.2025.101506

Sachiyo Yoneda , Kaori Yasuda , Bunzo Mikami , Teisuke Takita , Kiyoshi Yasukawa , Masahiro Hamada , Hiromasa Imaishi , Toshiyuki Sakaki , Shinichi Ikushiro

{"title":"Metabolism of simvastatin by Streptomyces griseolus CYP105A1 and its variants for the production of human simvastatin metabolites","authors":"Sachiyo Yoneda , Kaori Yasuda , Bunzo Mikami , Teisuke Takita , Kiyoshi Yasukawa , Masahiro Hamada , Hiromasa Imaishi , Toshiyuki Sakaki , Shinichi Ikushiro","doi":"10.1016/j.dmpk.2025.101506","DOIUrl":"10.1016/j.dmpk.2025.101506","url":null,"abstract":"<div><div><em>Streptomyces griseolus</em> CYP105A1 showed hydroxylation activity at 25- and 1α-positions of vitamin D<sub>3</sub> to produce an active form of vitamin D<sub>3</sub>. We have succeeded in dramatically increasing its activity by site-directed mutagenesis. We also found that CYP105A1 and its mutants metabolize various non-steroidal anti-inflammatory drugs. In this study, we attempted to metabolize simvastatin (SV), an HMG-CoA reductase inhibitor, by CYP105A1 mutants, and compared their metabolism with that by human CYP3A4. The SV was converted into multiple metabolites by the CYP105A1 variants CYP105A1-R84A and CYP105A1-R84A/M239A, with the latter exhibiting significantly higher activity than the former. The metabolites were estimated to be 6′-hydroxy-SV, 3′-hydroxy-SV, 3″-hydroxy SV, 3′,5′-dihydrodiol SV, and 6′-exomethylene SV. In addition, 6′-hydroxy-SV was non-enzymatically converted to 3′-hydroxy-SV under acidic conditions. The X-ray crystal structure of SV-bound CYP105A1-R84A suggested the formation of a 3′,4′-epoxide intermediate, from which 3′-hydroxy and 3′,5′-dihydrodiol SV were presumed to be generated non-enzymatically. It is noted that all of these metabolites have either been reported as SV metabolites formed by human CYP3A4 or were detected in the present study. Thus, CYP105A1-R84A/M239A appears to be highly useful for the production of human metabolites of SV.</div></div>","PeriodicalId":11298,"journal":{"name":"Drug Metabolism and Pharmacokinetics","volume":"65 ","pages":"Article 101506"},"PeriodicalIF":2.2,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145525903","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Important role of OATP in the liver disposition of ezetimibe and its consequent glucuronidation metabolite OATP在依泽可米及其后续糖醛酸化代谢产物的肝脏处理中的重要作用。

IF 2.2 4区医学

Drug Metabolism and Pharmacokinetics Pub Date : 2025-12-01 Epub Date: 2025-09-18 DOI: 10.1016/j.dmpk.2025.101503

Ying Su , Xinyi Zhang , Yiguo Jiang , Cheng Wang , Jianqing Ruan

引用次数: 0

A novel quantitative assessment of formed reactive metabolites by double trapping with [3H]glutathione and [14C]cyanide [3H]谷胱甘肽和[14C]氰化物双捕获形成的反应性代谢物的一种新的定量评估。

IF 2.2 4区医学

Drug Metabolism and Pharmacokinetics Pub Date : 2025-12-01 Epub Date: 2025-09-25 DOI: 10.1016/j.dmpk.2025.101504

Tomoyuki Kawachi , Tatsuki Fukami , Miki Nakajima

{"title":"A novel quantitative assessment of formed reactive metabolites by double trapping with [3H]glutathione and [14C]cyanide","authors":"Tomoyuki Kawachi , Tatsuki Fukami , Miki Nakajima","doi":"10.1016/j.dmpk.2025.101504","DOIUrl":"10.1016/j.dmpk.2025.101504","url":null,"abstract":"<div><div>Drug-induced liver injury often arises from reactive metabolites (RMs) produced in the liver, making it crucial to assess RM formation rates from drug candidates. Conventional assays using glutathione (GSH) effectively trap soft electrophilic RMs but fail to detect hard electrophiles. To address this, we developed a double trapping assay employing [<sup>3</sup>H]GSH and [<sup>14</sup>C]cyanide as soft and hard nucleophilic reagents, respectively. This assay was applied to 25 drugs chosen based on safety profiles. Eight drugs were exclusively trapped by [<sup>3</sup>H]GSH, while 11 were trapped by [<sup>14</sup>C]cyanide or both reagents, demonstrating that a double trapping assay provides a more comprehensive detection method for both soft and hard RMs. Multiplying RM formation rates by daily doses allowed almost complete differentiation between withdrawn/black boxed warning drugs and safer ones. Radio-LCMS analysis provided detailed insights into the substructures of drug candidates responsible for RM production. Interestingly, it was discovered that GSH-based assays sometimes fail to detect certain RMs due to the presence of dithiothreitol in commercial [<sup>3</sup>H]GSH. This study highlights the efficacy of the double trapping assay using [<sup>3</sup>H]GSH and [<sup>14</sup>C]cyanide in accurately and comprehensively detecting RMs. Furthermore, it offers valuable structural information to minimize RM formation during early drug discovery.</div></div>","PeriodicalId":11298,"journal":{"name":"Drug Metabolism and Pharmacokinetics","volume":"65 ","pages":"Article 101504"},"PeriodicalIF":2.2,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145667631","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

L-Type amino acid transporter 1-mediated developmental change of cerebral gabapentin distribution across the rat blood-brain barrier l型氨基酸转运蛋白1介导的脑加巴喷丁血脑屏障分布的发育变化。

IF 2.2 4区医学

Drug Metabolism and Pharmacokinetics Pub Date : 2025-12-01 Epub Date: 2025-08-29 DOI: 10.1016/j.dmpk.2025.101502

Hiroki Endo , Takeshi Sugouchi , Otaro Kobayashi , Yuma Tega , Yoshiyuki Kubo , Ken-ichi Hosoya , Shin-ichi Akanuma

{"title":"L-Type amino acid transporter 1-mediated developmental change of cerebral gabapentin distribution across the rat blood-brain barrier","authors":"Hiroki Endo , Takeshi Sugouchi , Otaro Kobayashi , Yuma Tega , Yoshiyuki Kubo , Ken-ichi Hosoya , Shin-ichi Akanuma","doi":"10.1016/j.dmpk.2025.101502","DOIUrl":"10.1016/j.dmpk.2025.101502","url":null,"abstract":"<div><div>Gabapentin is an anticonvulsant used in the pharmacotherapy of pediatric epilepsy. Differences in transporter-mediated cerebral drug/compound distribution across the blood-brain barrier (BBB) have been reported between neonates/infants, and adults. The purpose of our study was to comprehensively elucidate the transport of gabapentin across the BBB during childhood and its regulatory molecular systems. The cerebral distribution of [<sup>3</sup>H]gabapentin in 7-day-old rats was significantly lower than that in 42-day-old adult rats, suggesting weaker gabapentin transport in the BBB of neonates/infants than in adults. <em>In vivo</em> brain uptake and <em>in vitro</em> transport studies have indicated the involvement of transporters that accept large neutral amino acids in the cerebral gabapentin distribution across the BBB. In particular, an <em>in vitro</em> study using RNA interference suggested a major contribution of L-type amino acid transporter 1 (LAT1) to gabapentin transport across the BBB. In the brains of 7-day-old rats, the mRNA expression of LAT1 and the heavy chain of the 4F2 antigens (4F2hc), which forms a complex with LAT1, was reduced compared to that of 42-day-old rats. Consequently, it is suggested that a decrease in gabapentin distribution to the brain across the BBB contributes to the transcriptional reduction of cerebral LAT1 and 4F2hc.</div></div>","PeriodicalId":11298,"journal":{"name":"Drug Metabolism and Pharmacokinetics","volume":"65 ","pages":"Article 101502"},"PeriodicalIF":2.2,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145312571","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Japanese medicinal drug labeling for use in the clinical setting as informed by pharmacogenomic data on cytochrome P450 enzymes obtained from in silico studies. 根据从计算机研究中获得的细胞色素P450酶的药物基因组学数据，用于临床环境的日本药品标签。

IF 2.2 4区医学

Drug Metabolism and Pharmacokinetics Pub Date : 2025-10-01 Epub Date: 2025-05-29 DOI: 10.1016/j.dmpk.2025.101496

Yoichi Tanaka, Makiko Shimizu, Yoshiro Saito, Hiroshi Yamazaki

{"title":"Japanese medicinal drug labeling for use in the clinical setting as informed by pharmacogenomic data on cytochrome P450 enzymes obtained from in silico studies.","authors":"Yoichi Tanaka, Makiko Shimizu, Yoshiro Saito, Hiroshi Yamazaki","doi":"10.1016/j.dmpk.2025.101496","DOIUrl":"10.1016/j.dmpk.2025.101496","url":null,"abstract":"<p><p>Although the United States Food and Drug Administration has disclosed a list of drugs with pharmacogenomic biomarkers for drug labeling, there is limited information regarding pharmacogenomic-associated drugs in Japan. Such associations include genetic variants of uridine diphosphate glucuronosyltransferase 1A1 for irinotecan, nudix hydrolase 15 for thiopurine drugs, and cytochrome P450 (P450) 2C9 for siponimod. The effects of such genetic variants on drug concentrations are similar to those from drug interactions. Because of race and dosage differences, the relevance of pharmacogenomic associations in Asian populations requires confirmation. This white paper proposes that in vitro pharmacogenomic information can be used to predict human pharmacokinetics and to describe in drug labels the changes in blood concentrations by genetic variants. For P450 variants CYP2C9∗3, CYP2C19∗2, CYP2C19∗3, CYP2D6∗10, and CYP3A4∗16, we propose using the enzymatic activity parameters obtained from in vitro functional analysis of the drug-metabolizing enzymes for multiple substrate drugs to predict the effects of these variants on human pharmacokinetics. Consequently, in patients prescribed only a single drug, anything more than a \"moderate effect\" on plasma exposure should be mentioned as a caution in the drug labels; such effects are likely caused by enzyme polymorphisms resulting in similar effects to drug-drug interactions.</p>","PeriodicalId":11298,"journal":{"name":"Drug Metabolism and Pharmacokinetics","volume":"64 ","pages":"101496"},"PeriodicalIF":2.2,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144811933","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0