National Engineering Research Center for Miniaturized Detection Systems, School of Life Sciences, Northwest University, Xi'an, China.
Drug Metab Pharmacokinet. 2010;25(4):343-50. doi: 10.2133/dmpk.dmpk-10-rg-009.
Cytochrome P450 2C9 (CYP2C9) is a polymorphic enzyme responsible for the metabolism of many important drugs, including diclofenac. CYP2C93 and CYP2C913 are the principal variant alleles found in the Chinese population. CYP2C93 has been reported to reduce the metabolism of diclofenac and alter the extent of drug-drug interactions (DDIs). The effects of CYP2C913 on diclofenac metabolism are not well studied, and the influences of CYP2C913 on DDIs between diclofenac and clinical drugs are still unknown. In this study, CYP2C9.1 (the wildtype enzyme), CYP2C9.3 and CYP2C9.13 were expressed in yeast, and their metabolic kinetics for diclofenac 4'-hydroxylation were examined. From the in vitro data, we predicted a decrease in the ratio of diclofenac oral clearance (the ratio of oral clearance in subjects with variant CYP2C9 alleles to that in wildtype subjects (CL(oral)R)) in subjects carrying CYP2C93 or CYP2C913 alleles. Furthermore, we investigated the effects of these two alleles on diclofenac-drug interactions. The potentials of nine clinically used drugs to inhibit diclofenac 4'-hydroxylation catalyzed by the alleles were compared. Our results indicated that CYP2C9.3 and CYP2C9.13 can alter the CYP-inhibitory potencies of some tested drugs. In particular, CYP2C9.13 significantly weakened the inhibitory potencies of sulfaphenazole, fluvastatin, fluvoxamine and tranylcypromine. These data provide helpful guidelines for co-administration of diclofenac with other drugs in individuals carrying CYP2C93 and CYP2C9*13 alleles.
细胞色素 P450 2C9（CYP2C9）是一种负责代谢许多重要药物的多态酶，包括双氯芬酸。CYP2C93 和 CYP2C913 是中国人群中主要的变异等位基因。据报道，CYP2C93 会降低双氯芬酸的代谢，并改变药物相互作用（DDI）的程度。CYP2C913 对双氯芬酸代谢的影响尚未得到充分研究，CYP2C913 对双氯芬酸与临床药物之间的 DDI 的影响仍不清楚。在这项研究中，我们在酵母中表达了 CYP2C9.1（野生型酶）、CYP2C9.3 和 CYP2C9.13，并检测了它们对双氯芬酸 4'-羟化的代谢动力学。根据体外数据，我们预测携带 CYP2C93 或 CYP2C913 等位基因的个体中双氯芬酸口服清除率（变异 CYP2C9 等位基因个体的口服清除率与野生型个体的口服清除率之比（CL(oral)R））的比值会降低。此外，我们还研究了这两个等位基因对双氯芬酸-药物相互作用的影响。比较了九种临床常用药物对这些等位基因催化的双氯芬酸 4'-羟化的抑制潜力。我们的结果表明，CYP2C9.3 和 CYP2C9.13 可以改变一些测试药物对 CYP 的抑制能力。特别是，CYP2C9.13 显著减弱了磺胺苯吡唑、氟伐他汀、氟伏沙明和曲安西龙的抑制能力。这些数据为携带 CYP2C93 和 CYP2C9*13 等位基因的个体同时使用双氯芬酸和其他药物提供了有用的指导。
