Laboratory of Pharmaceutical Analysis and Drug Metabolism, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China.
Biopharm Drug Dispos. 2013 Jul;34(5):278-87. doi: 10.1002/bdd.1842. Epub 2013 Jun 3.
CYP2C8 plays an important role in the metabolism of various drugs, such as paclitaxel, repaglinide and ibuprofen. Polymorphisms in the CYP2C8 gene were shown to influence interindividual differences in the pharmacokinetics of paclitaxel, repaglinide and ibuprofen enantiomers. In this study, three CYP2C8 allelic variants (CYP2C8.2, CYP2C8.3 and CYP2C8.4) and wild-type CYP2C8 (CYP2C8.1) were co-expressed for the first time with human cytochrome P450 oxidoreductase (POR) and cytochrome b5 by using a baculovirus-assisted insect cell expression system. Further, the effects of genotype-phenotype correlations of CYP2C8 alleles on the metabolism of paclitaxel, repaglinide and ibuprofen enantiomers were evaluated. The CLint values of CYP2C8.2, CYP2C8.3 and CYP2C8.4 for paclitaxel were 47.7%, 64.3% and 30.2% of that of CYP2C8.1 (p<0.01). The CLint values of CYP2C8.2 and CYP2C8.4 for repaglinide were 77.9% and 80.2% of that of CYP2C8.1 (p<0.05), respectively, while the CLint value of CYP2C8.3 was 1.31-fold higher than that of CYP2C8.1 (p<0.05). The relative CLint values of CYP2C8.2, CYP2C8.3 and CYP2C8.4 were 110.5%, 72.3% and 49.7% of that of CYP2C8.1 and were 124.6%, 83.4% and 47.4% of that of CYP2C8.1 for R-ibuprofen and S-ibuprofen, respectively. Comparing hydroxylation by CYP2C8.1 and CYP2C8.3 resulted in higher and lower intrinsic clearance of repaglinide and ibuprofen enantiomers, respectively. These in vitro findings were consistent with the pharmacokinetics in volunteers who were heterozygous or homozygous carriers of CYP2C8*3. The results of this study provide useful information for predicting CYP2C8 phenotypes and may contribute to individualized drug therapy in the future.
CYP2C8 在各种药物的代谢中发挥着重要作用，如紫杉醇、瑞格列奈和布洛芬。CYP2C8 基因的多态性被证明会影响紫杉醇、瑞格列奈和布洛芬对映体的个体间药代动力学差异。在这项研究中，三种 CYP2C8 等位基因变体（CYP2C8.2、CYP2C8.3 和 CYP2C8.4）和野生型 CYP2C8（CYP2C8.1）首次通过杆状病毒辅助的昆虫细胞表达系统与人类细胞色素 P450 氧化还原酶（POR）和细胞色素 b5 共同表达。此外，还评估了 CYP2C8 等位基因的基因型-表型相关性对紫杉醇、瑞格列奈和布洛芬对映体代谢的影响。CYP2C8.2、CYP2C8.3 和 CYP2C8.4 对紫杉醇的 CLint 值分别为 CYP2C8.1 的 47.7%、64.3%和 30.2%（p<0.01）。CYP2C8.2 和 CYP2C8.4 对瑞格列奈的 CLint 值分别为 CYP2C8.1 的 77.9%和 80.2%（p<0.05），而 CYP2C8.3 的 CLint 值则比 CYP2C8.1 高 1.31 倍（p<0.05）。CYP2C8.2、CYP2C8.3 和 CYP2C8.4 的相对 CLint 值分别为 CYP2C8.1 的 110.5%、72.3%和 49.7%，分别为 CYP2C8.1 的 124.6%、83.4%和 47.4%，分别为 R-布洛芬和 S-布洛芬的。与 CYP2C8.1 和 CYP2C8.3 的羟化作用相比，瑞格列奈和布洛芬对映体的内在清除率更高和更低。这些体外发现与 CYP2C8*3 杂合或纯合携带者志愿者的药代动力学一致。本研究结果为预测 CYP2C8 表型提供了有用的信息，并可能有助于未来的个体化药物治疗。
