Evaluation of Recombinant CYP3A4 Variants on the Metabolism of Oxycodone In Vitro

被引：8

作者：

Cai, Yaoyao ^{[1
]}

Lin, Qianmeng ^{[2
,3
]}

Jin, Zhousheng ^{[1
]}

Xia, Fangfang ^{[1
]}

Ye, Yingchao ^{[1
]}

Xia, Yun ^{[4
]}

Papadimos, Thomas J. ^{[4
,5
]}

Wang, Quanguang ^{[1
]}

Hu, Guoxin ^{[2
]}

Cai, Jianping ^{[6
]}

Chen, Limei ^{[1
]}

机构：

[1] Wenzhou Med Univ, Affiliated Hosp 1, Dept Anesthesiol, Wenzhou 325035, Zhejiang, Peoples R China

[2] Wenzhou Med Univ, Sch Pharmaceut Sci, Wenzhou 325035, Zhejiang, Peoples R China

[3] Cent South Univ, XiangYa Hosp, Dept Oncol, NHC Key Lab Canc Prote, Changsha 410008, Peoples R China

[4] Ohio State Univ, Dept Anesthesiol, Wexner Med Ctr, Columbus, OH 43210 USA

[5] Ohio State Univ, Crit Care Sect, Wexner Med Ctr, Columbus, OH 43210 USA

[6] Beijing Hosp, Natl Ctr Gerontol, Minist Hlth MOH, Key Lab Geriatr, Beijing 100730, Peoples R China

来源：

CHEMICAL RESEARCH IN TOXICOLOGY | 2021年 / 34卷 / 01期

基金：

中国国家自然科学基金;

关键词：

ALLELIC VARIANTS; FUNCTIONAL-CHARACTERIZATION; GENETIC POLYMORPHISMS; NIFEDIPINE OXIDASE; HUMAN LIVER; CYTOCHROME-P450; PHARMACOKINETICS; OXIDATION; VARIABILITY; CYP2D6;

D O I：

10.1021/acs.chemrestox.0c00361

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Cytochrome P450 3A4 is a highly polymorphic enzyme and metabolizes approximately 40%-60% of therapeutic drugs. Its genetic polymorphism may significantly affect the expression and function of CYP3A4 resulting in alterations of the pharmacokinetics and pharmacodynamics of the CYP3A4-mediated drugs. The purpose of this study was to evaluate the catalytic activities of 30 CYP3A4 nonsynonymous variants and wild type toward oxycodone in vitro. CYP3A4 proteins were incubated with oxycodone for 30 min at 37 degrees C and the reaction was terminated by cooling to -80 degrees C immediately. Ultraperformance liquid chromatography tandem mass-spectrometry was used to analyze noroxycodone, and kinetic parameters Km, Vmax, and intrinsic clearance (Vmax/Km) of noroxycodone were also determined. Compared with CYP3A4.1, 24 CYP3A4 variants (CYP3A4.2-.5, -.7-.16, -.18 and -.19, -.23 and -.24, -.28 and -.29, and -.31-.34) exhibited significantly decreased relative clearance values (from 4.82% +/- 0.31% to 80.98% +/- 5.08%), whereas CYP3A4.6, -.17, -.20, -.21, -.26, and -.30 displayed no detectable enzyme activity. As the first study of these alleles for oxycodone metabolism in vitro, results of this study may provide insight into establishing the genotype-phenotype relationship for oxycodone and serve as a reference for clinical administrators and advance the provision of personalized precision medicine.

引用

页码：103 / 109

页数：7

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