Michaud V, Kreutz Y, Skaar T, Ogburn E, Thong N, Flockhart D A, Desta Z
Division of Clinical Pharmacology, Department of Medicine, School of Medicine, Indiana University, Indianapolis, IN, USA.
Pharmacogenomics J. 2014 Apr;14(2):151-9. doi: 10.1038/tpj.2013.17. Epub 2013 Apr 30.
Efavirenz increases CYP2C19- and CYP3A-mediated omeprazole metabolism. We hypothesized that CYP2C19 and CYP2B6 genetic polymorphisms influence the extent of induction of omeprazole metabolism by efavirenz. Healthy subjects (n=57) were administered a single 20 mg oral dose of omeprazole on two occasions: with a single 600 mg efavirenz dose; and after a 17-day treatment with efavirenz (600 mg per day). DNA was genotyped for CYP2C19*2, *3 and 17 alleles and CYP2B66, *4 and *9 alleles using Taqman assays. Omeprazole, its enantiomers and metabolites were measured by liquid chromatography/tandem mass spectrometry. Our results showed that efavirenz increased omeprazole clearances in all CYP2C19 genotypes in non-stereoselective manner, but the magnitude of induction was genotype dependent. Metabolic ratios of 5-hydroxylation of omeprazole were reduced in extensive and intermediate metabolizers of CYP2C19 (P<0.05). No significant associations were observed between CYP2B6 genotypes and induction by efavirenz on omeprazole metabolism. Our data indicate how interplays between drug interactions and CYP2C19 genetic variations may influence systemic exposure of CYP2C19 substrates.
依非韦伦可增加细胞色素P450 2C19（CYP2C19）和细胞色素P450 3A（CYP3A）介导的奥美拉唑代谢。我们推测CYP2C19和细胞色素P450 2B6（CYP2B6）基因多态性会影响依非韦伦对奥美拉唑代谢的诱导程度。健康受试者（n = 57）分两次口服单剂量20 mg奥美拉唑：一次与单剂量600 mg依非韦伦同时服用；另一次在接受依非韦伦（每日600 mg）治疗17天后服用。使用Taqman分析对CYP2C19 *2、3和17等位基因以及CYP2B6 *6、4和9等位基因进行基因分型。采用液相色谱/串联质谱法测定奥美拉唑及其对映体和代谢产物。我们的结果表明，依非韦伦以非立体选择性方式增加了所有CYP2C19基因型中奥美拉唑的清除率，但诱导程度因基因型而异。在CYP2C19的广泛代谢者和中间代谢者中，奥美拉唑5-羟化的代谢比降低（P<0.05）。未观察到CYP2B6基因型与依非韦伦对奥美拉唑代谢的诱导之间存在显著关联。我们的数据表明药物相互作用与CYP2C19基因变异之间的相互作用可能如何影响CYP2C19底物的全身暴露。
