Drug Metabolism and Pharmacokinetics最新文献

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

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 : 2025-08-29 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":"2025-08-29","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

Construction of refined CYP2D6-Template system for studies of its metabolism and inhibition 精制cyp2d6 -模板体系的构建及其代谢和抑制研究

IF 2.2 4区医学

Drug Metabolism and Pharmacokinetics Pub Date : 2025-08-01 DOI: 10.1016/j.dmpk.2025.101499

Yasushi Yamazoe , Norie Murayama , Kouichi Yoshinari

{"title":"Construction of refined CYP2D6-Template system for studies of its metabolism and inhibition","authors":"Yasushi Yamazoe , Norie Murayama , Kouichi Yoshinari","doi":"10.1016/j.dmpk.2025.101499","DOIUrl":"10.1016/j.dmpk.2025.101499","url":null,"abstract":"<div><div>The previously reported Template system for the prediction of human CYP2D6-mediated reactions (Drug Metab Dispos 40 486-96, 2012) has been refined with the introduction of ideas of allowable width, Trigger∗-residue and the residue-initiated movement of ligands in the active site. These ideas are in common with published Template systems for human CYP1A1, CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP2E1, CYP2J2, and CYP3A4/5/7 (Drug Metab Pharmacokinet 2016, 2019, 2020, 2021, 2022, 2023, and 2024, Food Safety 2024). Total 616 reactions of 441 distinct chemicals reported as CYP2D6 ligands were examined in the refined CYP2D6-Template system. From their placements on the refined Template and rules for interaction modes, verifications of good and poor substrates, regio/stereo-selectivity, and inhibition became faithfully available for these ligands. A comparison of the placements suggested key interactions with Shelf and Left-end for ligand accommodations on the refined CYP2D6-Template. Shelf-surrounding of ligands was also proposed as a cause of their intense inhibitions. The refined CYP2D6-Template system will thus offer reliable estimations of this human CYP catalyses toward ligands of diverse structures, together with their deciphering information to lead to judgments of regioselective metabolisms.</div></div>","PeriodicalId":11298,"journal":{"name":"Drug Metabolism and Pharmacokinetics","volume":"63 ","pages":"Article 101499"},"PeriodicalIF":2.2,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144842811","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

Impact of degradation in subcutaneous tissue and lymphatic fluid on absorption of Fc-fusion proteins following subcutaneous administration 皮下给药后皮下组织和淋巴液降解对fc融合蛋白吸收的影响

IF 2.2 4区医学

Drug Metabolism and Pharmacokinetics Pub Date : 2025-07-17 DOI: 10.1016/j.dmpk.2025.101500

Miki Yokoyama, Eiko Suzuki, Daisuke Nakai

{"title":"Impact of degradation in subcutaneous tissue and lymphatic fluid on absorption of Fc-fusion proteins following subcutaneous administration","authors":"Miki Yokoyama, Eiko Suzuki, Daisuke Nakai","doi":"10.1016/j.dmpk.2025.101500","DOIUrl":"10.1016/j.dmpk.2025.101500","url":null,"abstract":"<div><div>Subcutaneous administration is widely used as a clinical administration route for Fc-fusion proteins. However, predicting bioavailability (BA) in humans after subcutaneous administration is challenging due to multiple factors involved in the absorption process. This study aimed to elucidate the impact of degradation on the BA of Fc-fusion proteins. We established two measurement methods for each Fc-fusion protein: the Fc/Fc method, which recognizes the Fc region; and the Protein/Fc method, which recognizes both protein and Fc region. BA of dulaglutide and romiplostim in rats were 80.1 % and 99.4 % by the Fc/Fc method, and 35.0 % and 55.5 % by the Protein/Fc method, respectively. The lower BA with the Protein/Fc method indicates that the protein region undergoes degradation during the absorption process. In stability studies with rat skin homogenates and lymphatic fluid, degradation of the protein region for both dulaglutide and romiplostim was confirmed, which was inhibited by protease inhibitors. In contrast, abatacept and etanercept were stable in skin homogenates and lymphatic fluid, and their BA in rats were comparable between the Fc/Fc and Protein/Fc methods. This study indicates that the presence or absence of protease-mediated degradation during the absorption process is one of the factors affecting the BA of Fc-fusion proteins.</div></div>","PeriodicalId":11298,"journal":{"name":"Drug Metabolism and Pharmacokinetics","volume":"64 ","pages":"Article 101500"},"PeriodicalIF":2.2,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144988521","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

Investigation of an OATP1B inhibitory effect by a cyclic peptide using the endogenous biomarker coproporphyrin-I in monkeys 利用内源性生物标志物coproporphyrin-I研究环肽对猴子OATP1B的抑制作用

IF 2.7 4区医学

Drug Metabolism and Pharmacokinetics Pub Date : 2025-06-03 DOI: 10.1016/j.dmpk.2025.101497

Hiromi Sawada , Yasuto Kido , Makoto Iwasaki , Kimiko Nishida , Kei Mayumi , Ryosuke Watari

{"title":"Investigation of an OATP1B inhibitory effect by a cyclic peptide using the endogenous biomarker coproporphyrin-I in monkeys","authors":"Hiromi Sawada , Yasuto Kido , Makoto Iwasaki , Kimiko Nishida , Kei Mayumi , Ryosuke Watari","doi":"10.1016/j.dmpk.2025.101497","DOIUrl":"10.1016/j.dmpk.2025.101497","url":null,"abstract":"<div><div>Peptide drugs are expected to be a new modality that will replace traditional small molecule drugs. As the number of approved peptide drugs increases, they are being co-administered with various drugs, but there is a limited number of reports on their drug-drug interaction (DDI) in both <em>in vitro</em> and <em>in vivo</em> (clinical) studies. In this study, we investigated the transporter inhibitory potential of Compound A, a macrocyclic peptide (3.5 kDa) for the treatment of pain. We found that Compound A exhibited a strong inhibitory effect on the organic anion transporting polypeptide (OATP) 1B in an <em>in vitro</em> study. To assess the <em>in vivo</em> OATP1B inhibitory potential, Compound A was intravenously or subcutaneously administered to monkeys, and the plasma concentration of coproporphyrin-I (CP-I), an endogenous biomarker of OATP1B, was determined. Compound A markedly increased the CP-I concentration in monkeys. A semi-mechanistic pharmacokinetic model analysis using the CP-I concentration revealed that Compound A is a highly potent <em>in vivo</em> OATP1B inhibitor (<em>in vivo</em> K<sub>i, OATP1B</sub>: 59.9 ng/mL as total plasma concentration). Our findings suggest that even peptides with a large molecular weight can cause DDI. These results offer valuable information for the further development of DDI guidelines for peptides.</div></div>","PeriodicalId":11298,"journal":{"name":"Drug Metabolism and Pharmacokinetics","volume":"63 ","pages":"Article 101497"},"PeriodicalIF":2.7,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144549742","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

Development of an in vitro Metabolic Dysfunction-Associated Steatohepatitis (MASH) model to study hepatic transporters 建立体外代谢功能障碍相关脂肪性肝炎（MASH）模型研究肝脏转运体

IF 2.7 4区医学

Drug Metabolism and Pharmacokinetics Pub Date : 2025-06-01 DOI: 10.1016/j.dmpk.2025.101123

Sarina Kyburz , William A. Murphy , Thomas Kralj , John K. Fallon , Jacqueline B. Tiley , Kim L.R. Brouwer

引用次数: 0

Development and qualification of an in vitro assay to determine target mediated internalization of TREM2 receptor specific antibodies for TMDD assessment 开发和鉴定用于TMDD评估的TREM2受体特异性抗体靶介导内化的体外测定方法

IF 2.7 4区医学

Drug Metabolism and Pharmacokinetics Pub Date : 2025-06-01 DOI: 10.1016/j.dmpk.2025.101134

Thomas Kraft , Anna-Lena Bolender , Aman Padamsey , Erich Koller , Markus Britschgi , Jens Niewoehner , Hans Peter Grimm

引用次数: 0

Evaluation for biotransformation of antibody-peptide conjugates using native mass spectrometry 利用天然质谱法评价抗体-肽偶联物的生物转化

IF 2.7 4区医学

Drug Metabolism and Pharmacokinetics Pub Date : 2025-06-01 DOI: 10.1016/j.dmpk.2025.101135

Hiraku Hagita, Sahana Iwamura, Tomoki Suzuki, Kenichi Sasahara, Keisuke Maki, Yosuke Kaneko

引用次数: 0

How do i build an ‘Ideal’ PBPK model if my drug is either a substrate or inducer 如果我的药物是底物或诱导剂，我如何建立一个“理想的”PBPK模型

IF 2.7 4区医学

Drug Metabolism and Pharmacokinetics Pub Date : 2025-06-01 DOI: 10.1016/j.dmpk.2025.101061

Ryuta Asaumi

引用次数: 0

Novel mechanisms of drug-metabolizing hydrolases regulating the toxicity caused by reactive metabolites 药物代谢水解酶调节活性代谢物毒性的新机制

IF 2.7 4区医学

Drug Metabolism and Pharmacokinetics Pub Date : 2025-06-01 DOI: 10.1016/j.dmpk.2025.101066

Tatsuki Fukami

引用次数: 0