Yin Sheng-Ju, Qi Hui-Min, Wang Xin, Zhang Pu, Lu Yuan, Wei Min-Ji, Li Pu, Qi Guang-Zhao, Lou Ya-Qing, Lu Chuang, Zhang Guo-Liang
aDepartment of Pharmacology,School of Basic Medical Sciences, Peking University bDepartment of Pharmacokinetics, Institute of Clinical Pharmacology, Peking University First Hospital, Beijing, China cDepartment of Drug Metabolism & Pharmacokinetics, Biogen, Cambridge, Massachusetts, USA.
Pharmacogenet Genomics. 2017 Apr;27(4):125-134. doi: 10.1097/FPC.0000000000000265.
Pioglitazone is a thiazolidinedione antihyperglycemic drug with insulin-sensitizing properties. We investigated whether the variant genotypes of cytochrome P450 2C8 (CYP2C8), CYP2C9, CYP3A5 and transporter ABCB1 influence the pharmacokinetic phenotype of the substrate pioglitazone in Chinese individuals.
Single-nucleotide polymorphisms were determined by the PCR-restriction fragment length polymorphism method in 244 (CYP2C8 and CYP2C9) healthy Chinese Han individuals. After a single oral dose of 30 mg pioglitazone, the plasma concentrations of the parent drug and of two major active metabolites M-III and M-IV were measured using a validated LC-MS/MS in 21 (genotyping CYP3A5 and ABCB1) of these 244 volunteers.
The results confirmed that the unique frequencies of CYP2C82 (0.0%), CYP2C83 (0.0%), and CYP2C92 (0.0%) alleles were significantly different from those reported in Whites and Africans, and there were only 10 variant CYP2C91/3 heterozygous (CYP2C93 carriers) among 244 Chinese individuals. These results were similar to those reported in Asian ethnic populations, including the Chinese. Unexpectedly, the pioglitazone AUC0-48 in CYP2C93 carriers was lower (50.8%), whereas the AUC0-48 ratios of metabolites M-III/pioglitazone and M-IV/pioglitazone increased to 134.3 and 155.8%, respectively, compared with the wild-type CYP2C91/1 homozygous. Moreover, this phenomenon was not observed in individuals with genetic variants of CYP3A53 and ABCB1 (C1236T).
The present research suggests that the CYP2C8, CYP3A5, and ABCB1 genes play no significant role in the interindividual variation of pioglitazone pharmacokinetics, whereas CYP2C9*3 carriers are likely to accelerate the metabolism of this antidiabetic drug in the Chinese Han ethnic population.
吡格列酮是一种具有胰岛素增敏特性的噻唑烷二酮类降糖药物。我们研究了细胞色素P450 2C8（CYP2C8）、CYP2C9、CYP3A5和转运体ABCB1的变异基因型是否会影响中国人群中底物吡格列酮的药代动力学表型。
采用聚合酶链反应-限制性片段长度多态性方法对244名健康中国汉族个体（针对CYP2C8和CYP2C9）进行单核苷酸多态性检测。在单次口服30毫克吡格列酮后，使用经过验证的液相色谱-串联质谱法对这244名志愿者中的21名（对CYP3A5和ABCB1进行基因分型）测定母体药物以及两种主要活性代谢物M-III和M-IV的血浆浓度。
结果证实，CYP2C82（0.0%）、CYP2C83（0.0%）和CYP2C92（0.0%）等位基因的独特频率与白种人和非洲人中报道的频率有显著差异，并且在244名中国个体中仅有10名CYP2C91/3杂合子（CYP2C93携带者）。这些结果与包括中国人在内的亚洲种族人群中报道的结果相似。出乎意料的是，与野生型CYP2C91/1纯合子相比，CYP2C93携带者中吡格列酮的AUC0-48较低（50.8%），而代谢物M-III/吡格列酮和M-IV/吡格列酮的AUC0-48比值分别增至134.3%和155.8%。此外，在CYP3A53和ABCB1（C1236T）基因变异个体中未观察到这种现象。
本研究表明，CYP2C8、CYP3A5和ABCB1基因在吡格列酮药代动力学的个体间差异中不起显著作用，而CYP2C9*3携带者可能会加速中国汉族人群中这种抗糖尿病药物的代谢。
