Department of Clinical Pharmacology, Yonsei University Severance Hospital, Seoul, Korea.
Drug Metab Pharmacokinet. 2013;28(3):196-202. doi: 10.2133/dmpk.dmpk-12-rg-068. Epub 2012 Sep 25.
Pitavastatin, a 3-hydroxyl-3-methylglutaryl-coenzyme A reductase inhibitor is distributed to the liver, a target organ of action and excreted mainly into the bile. To investigate the impact of influx (OATP1B1) and efflux (MRP2, BCRP) transporter alleles on its disposition, the pharmacokinetic (PK) parameters were compared among the following groups: SLCO1B1 (15 carrier and non-carrier), ABCC2 (G1249A, C3972T, C-24T, G1549A, and G1774T), and ABCG2 (C421A) single nucleotide polymorphisms in 45 healthy Korean volunteers. Pitavastatin AUC(last) was higher in individuals carrying the SLCO1B115 allele than those not carrying it (144.1 ± 55.3 vs. 84.7 ± 25.7 h·ng/mL [mean ± SD], p = 0.002). The AUC(last) varied significantly according to the ABCC2 C-24T allele (103.4 ± 42.2, 80.2 ± 23.8, and 39.0 h·ng/mL in CC, CT and TT, respectively; p = 0.027). Other SNPs of ABCC2 and ABCG2 were not significant. The effect of these transporters and body weight on the AUC(last) and C(max) were tested, and only SLCO1B1 and ABCC2 C-24T genotypes were significant factors by analysis of covariance. These variants accounted for almost 50% of the variation in AUC(last) and C(max) of pitavastatin. Therefore, ABCC2 C-24T was significantly associated with pitavastatin human PK when the known effect of SLCO1B1*15 was also considered.
匹伐他汀是一种 3-羟基-3-甲基戊二酰基辅酶 A 还原酶抑制剂，分布于肝脏（作用靶器官），主要经胆汁排泄。为了研究摄取（OATP1B1）和外排（MRP2、BCRP）转运体等位基因对其处置的影响，比较了以下 45 名韩国健康志愿者的以下各组的药代动力学（PK）参数：SLCO1B1（15 携带者和非携带者）、ABCC2（G1249A、C3972T、C-24T、G1549A 和 G1774T）和 ABCG2（C421A）单核苷酸多态性。与不携带 SLCO1B115 等位基因的个体相比，携带该等位基因的个体的匹伐他汀 AUC(last)更高（144.1 ± 55.3 比 84.7 ± 25.7 h·ng/mL [平均值 ± SD]，p = 0.002）。ABCC2 C-24T 等位基因使 AUC(last)显著变化（CC、CT 和 TT 基因型的 AUC(last)分别为 103.4 ± 42.2、80.2 ± 23.8 和 39.0 h·ng/mL；p = 0.027）。ABCC2 和 ABCG2 的其他 SNP 没有显著差异。还测试了这些转运体和体重对 AUC(last)和 C(max)的影响，只有 SLCO1B1 和 ABCC2 C-24T 基因型是协方差分析的显著因素。这些变体几乎解释了匹伐他汀 AUC(last)和 C(max)的 50%的变异性。因此，当考虑到已知的 SLCO1B1*15 影响时，ABCC2 C-24T 与匹伐他汀的人体 PK 显著相关。
