دورية أكاديمية
Interplay of UDP-Glucuronosyltransferase and CYP2C8 for CYP2C8 Mediated Drug Oxidation and Its Impact on Drug-Drug Interaction Produced by Standardized CYP2C8 Inhibitors, Clopidogrel and Gemfibrozil.
| العنوان: | Interplay of UDP-Glucuronosyltransferase and CYP2C8 for CYP2C8 Mediated Drug Oxidation and Its Impact on Drug-Drug Interaction Produced by Standardized CYP2C8 Inhibitors, Clopidogrel and Gemfibrozil. |
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| المؤلفون: | Iga K; Pharmaceutical Research and Technology Unit, R & D Division, Pre-formulation Department, Towa Pharmaceutical Co., Ltd, Kyoto Research Park KISTIC #202, 134, Chudoji Minami-machi, Shimogyo-ku, Kyoto, 600-8813, Japan. kiga2020@outlook.jp., Kiriyama A; Department of Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Doshisha Women's College of Liberal Arts, Kodo Kyotanabe-shi, Kyoto, 610-0395, Japan. |
| المصدر: | Clinical pharmacokinetics [Clin Pharmacokinet] 2024 Jan; Vol. 63 (1), pp. 43-56. Date of Electronic Publication: 2023 Nov 03. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: Country of Publication: Switzerland NLM ID: 7606849 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1179-1926 (Electronic) Linking ISSN: 03125963 NLM ISO Abbreviation: Clin Pharmacokinet Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: [Switzerland] : Adis, part of Springer Science+Business Media Original Publication: New York, ADIS Press. |
| مواضيع طبية MeSH: | Gemfibrozil*/pharmacology , Cytochrome P-450 CYP2C8 Inhibitors*/pharmacology, Humans ; Cytochrome P-450 CYP2C8/metabolism ; Clopidogrel ; Glucuronosyltransferase ; Drug Interactions ; Uridine Diphosphate |
| مستخلص: | Background and Objective: Early investigations into drug-drug interactions (DDIs) involving cytochrome P450 2C8 (CYP2C8) have highlighted the complexity of interactions between CYP2C8 substrate drugs, including montelukast, desloratadine, pioglitazone, repaglinide, and cerivastatin (the latter two being OATP1B1 substrates), and standardized CYP2C8 inhibitors such as clopidogrel (Clop) and gemfibrozil (Gem). These interactions have proven challenging to predict based solely on simple CYP inhibition. A hypothesis has emerged suggesting that these substrate drugs first distribute to UDP-glucuronosyltransferase (UGT) before undergoing oxidation by CYP2C8, resulting in bidirectional elimination. The process of drug distribution to UGT is believed to significantly impact these DDIs. This study aims to explore the intricate interplay between UGT and CYP2C8 in the context of DDIs involving CYP2C8 substrates affected by Clop and Gem. Methods: Plasma-level data for the unchanged drug and its metabolite, drawn from the respective literature, formed the basis of our analysis. We evaluated the enzymatic inhibitory activities of DDIs and utilized simulations to estimate plasma levels of the unchanged victim drug and its metabolite in each DDI. This was accomplished by employing a functional relationship that considered the fractional contributions of CYP2C8 and UGT to clearance, perpetrator-specific inhibitory activities against CYP2C8, and drug distribution to UGT. Results: Our findings emphasize the pivotal role of UGT-mediated distribution in the context of CYP2C8 substrate metabolism, particularly in the complex DDIs induced by Clop and Gem. In these DDIs, Gem exerts inhibitory effects on both UGT and CYP2C8, whereas Clop (specifically its metabolite, Clop-COOH) solely targets CYP2C8. Importantly, the inhibition of CYP2C8 by both Clop and Gem is achieved through a non-competitive mechanism, driven by the actions of their acyl-glucuronides. Clop and Gem exhibit inhibition activities accounting for 85% (pA Conclusion: These findings substantially enhance our comprehension of CYP2C8-mediated oxidation and DDIs, holding crucial implications for drug development and the planning of clinical trials involving these inhibitors. (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.) |
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| المشرفين على المادة: | Q8X02027X3 (Gemfibrozil) EC 1.14.14.1 (Cytochrome P-450 CYP2C8) A74586SNO7 (Clopidogrel) 0 (Cytochrome P-450 CYP2C8 Inhibitors) EC 2.4.1.17 (Glucuronosyltransferase) 58-98-0 (Uridine Diphosphate) EC 1.14.14.1 (CYP2C8 protein, human) |
| تواريخ الأحداث: | Date Created: 20231103 Date Completed: 20240115 Latest Revision: 20240416 |
| رمز التحديث: | 20240416 |
| DOI: | 10.1007/s40262-023-01322-7 |
| PMID: | 37921907 |
| قاعدة البيانات: | MEDLINE |
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Full Text Finder | تدمد: | 1179-1926 |
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| DOI: | 10.1007/s40262-023-01322-7 |