重新评估人类和犬 CYP3A 指数反应在苯二氮䓬类药物和甾体激素之间的体外研究。
Reevaluate In Vitro CYP3A Index Reactions of Benzodiazepines and Steroids between Humans and Dogs.
机构信息
Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy (Q.W., Y.H., C.W., W.W., K.L.), and Institute of Clinical Pharmacology, West China Hospital (J.M.), Sichuan University, Chengdu, China; Chengdu Health-Balance Medical Technology Co., Ltd., Chengdu, China (L.G., W.Z., K.L.); State Key Laboratory of Drug Delivery Technology and Pharmacokinetics, Tianjin Institute of Pharmaceutical Research, Tianjin, China (C.L.); and School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong, China (W.J.).
Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy (Q.W., Y.H., C.W., W.W., K.L.), and Institute of Clinical Pharmacology, West China Hospital (J.M.), Sichuan University, Chengdu, China; Chengdu Health-Balance Medical Technology Co., Ltd., Chengdu, China (L.G., W.Z., K.L.); State Key Laboratory of Drug Delivery Technology and Pharmacokinetics, Tianjin Institute of Pharmaceutical Research, Tianjin, China (C.L.); and School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong, China (W.J.)
出版信息
Drug Metab Dispos. 2022 Jun;50(6):741-749. doi: 10.1124/dmd.122.000864. Epub 2022 Mar 29.
Cytochrome P450 3A (CYP3A), the most important class of drug-metabolizing enzymes, participates in the metabolism of half of clinically used drugs. The CYP3A index reactions of dogs, one of the most widely used preclinical nonrodent species, are still poorly understood. This work evaluated the activity and selectivity of 10 CYP3A index reactions, including midazolam (MDZ) 1'- and 4-hydroxylation, alprazolam (APZ) and triazolam (TRZ) - and 4-hydroxylation, testosterone (T) 6-hydroxylation, lithocholate (LCA) 6-hydroxylation, deoxycholate (DCA) 1- and 5-hydroxylation, with quantitative reaction phenotyping and kinetic analysis in human and canine recombinant CYP enzymes (rCYPs). In human studies, all reactions are reconfirmed as mixed index reactions of CYP3A with minor contributions from non-CYP3A isoforms. In canine studies, all reactions are also primarily catalyzed by CYP3A12 with lower contributions from CYP3A26. However, the canine CYP2B11 appreciably contributes to the hydroxylation of benzodiazepines except for APZ 4-hydroxylation. The canine CYP3A isoforms have lower activity than human isoforms toward T 6-hydroxylation and LCA 6-hydroxylation and both substrates undergo non-CYP3A catalyzed side reactions. DCA 1- and 5-hydroxylation are validated as the CYP3A index reactions in both humans and dogs with limited non-CYP3A contributions and side reactions. In conclusion, this work provides a comprehensive overview for the selectivity and activity of in vitro CYP3A index reactions in humans and dogs. The validated CYP3A index reactions between humans and dogs may benefit future practices in drug metabolism and drug interaction studies. SIGNIFICANCE STATEMENT: Dogs are one of the most important nonrodent animals with limited studies of cytochrome P450 enzymes than humans. This work provides the most comprehensive quantitative data to date for the selectivity and activity of CYP3A index reactions in humans and dogs. The canine CYP2B11 was found to appreciably contribute to hydroxylation of midazolam, alprazolam and triazolam, the well-known probes for human CYP3A. Deoxycholate 1- and 5-hydroxylation are validated as the CYP3A index reactions in both humans and dogs.
细胞色素 P450 3A（CYP3A）是最重要的药物代谢酶类之一，参与了一半的临床应用药物的代谢。犬 CYP3A 指数反应，作为最广泛使用的非啮齿类临床前动物之一，仍然知之甚少。本研究评估了 10 种 CYP3A 指数反应的活性和选择性，包括咪达唑仑（MDZ）1'和 4-羟化、阿普唑仑（APZ）和三唑仑（TRZ）-和 4-羟化、睾酮（T）6-羟化、胆酸（LCA）6-羟化、脱氧胆酸（DCA）1-和 5-羟化，采用定量反应表型和犬及人重组 CYP 酶（rCYPs）的动力学分析。在人体研究中，所有反应均被重新确认为 CYP3A 的混合指数反应，非 CYP3A 同工酶也有少量贡献。在犬类研究中，所有反应也主要由 CYP3A12 催化，CYP3A26 的贡献较低。然而，犬 CYP2B11 除了 APZ 4-羟化外，对苯二氮䓬类化合物的羟化作用贡献较大。犬 CYP3A 同工酶对 T 6-羟化和 LCA 6-羟化的活性低于人同工酶，并且这两种底物都发生非 CYP3A 催化的副反应。DCA 1-和 5-羟化被验证为人类和犬类的 CYP3A 指数反应，其非 CYP3A 贡献和副反应有限。总之，本研究全面概述了人类和犬 CYP3A 指数反应的选择性和活性。人类和犬 CYP3A 指数反应的验证可能有助于未来药物代谢和药物相互作用研究中的应用。意义：犬是仅次于人类的最重要的非啮齿类动物之一，对细胞色素 P450 酶的研究比人类要少。本研究提供了迄今为止最全面的定量数据，用于评估人类和犬 CYP3A 指数反应的选择性和活性。犬 CYP2B11 被发现对咪达唑仑、阿普唑仑和三唑仑的羟化作用有明显贡献，这三种物质是人类 CYP3A 的常用探针。脱氧胆酸 1-和 5-羟化被验证为人类和犬类的 CYP3A 指数反应。
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