Effects of CYP3A4 Variants on Methadone Metabolism In Vitro.

Autor: Wang CC; Department of Pharmacy, Quzhou KeCheng People's Hospital, Quzhou, Zhejiang, China., Zhang ML; Department of Pharmacy, Quzhou KeCheng People's Hospital, Quzhou, Zhejiang, China., Xu YD; Department of Pharmacy, Quzhou KeCheng People's Hospital, Quzhou, Zhejiang, China., Hu GX; Institute of Molecular Toxicology and Pharmacology, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China., Cai JP; Institute of Molecular Toxicology and Pharmacology, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China.; The Key Laboratory of Geriatrics, Beijing Hospital & Beijing Institute of Geriatrics, Ministry of Health, Beijing, China., Lan T; Department of Pharmacy, The Quzhou Affiliated Hospital of Wenzhou Medical University, Quzhou People's Hospital, Quzhou, Zhejiang, China., Bai YF; Department of Clinical Laboratory, The Quzhou Affiliated Hospital of Wenzhou Medical University, Quzhou People's Hospital, Quzhou, Zhejiang, China.
Jazyk: angličtina
Zdroj: Biomedical chromatography : BMC [Biomed Chromatogr] 2025 Jan; Vol. 39 (1), pp. e6056.
DOI: 10.1002/bmc.6056
Abstrakt: In hepatic drug metabolism, cytochrome P450 (CYP450) enzymes, particularly CYP3A4, catalyze the majority of drug biotransformations, accounting for over 50% of the CYP450 family's metabolic capacity. This study aimed to assess the catalytic efficiency of 22 CYP3A4 allelic variants on the in vitro oxidative metabolism of methadone. We utilized a baculovirus-insect cell expression system to produce recombinant CYP3A4 variants and subsequently assessed their catalytic activity in the N-demethylation of methadone. Of the 23 tested CYP3A4 allelic variants, CYP3A4*1 represents the wild type. Compared with CYP3A4*1, 12 variants displayed significantly lower intrinsic clearance of methadone, while 3 variants showed increased intrinsic clearance of methadone. Additionally, six variants demonstrated no significant difference in intrinsic clearance of methadone compared to CYP3A4*1, and one variant showed no detectable expression. Our evaluation of the enzymatic activity of CYP3A4 gene polymorphisms on methadone can aid in the personalized clinical use of methadone and facilitate the investigation into the relationship between genetic variations and clinical phenotypes.
(© 2025 John Wiley & Sons Ltd.)
Databáze: MEDLINE
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