Effect of OATPIBI (SLCOIBI) variant alleles on the pharmacokinetics of pitavastatin in healthy volunteers
Effect of OATPIBI (SLCOIBI) variant alleles on the pharmacokinetics of pitavastatin in healthy volunteers
复制标题
DOI：
10.1016/j.clpt.2005.07.003
复制
发表时间：
2005-10-01
影响因子：
6.7
通讯作者：
Jang, IJ
中科院分区：
文献类型：
--
作者：
Chung, JY;Cho, JY;Jang, IJ
背景匹伐他汀是一种新开发的有效的3-羟基-3-甲基戊二酰辅酶A还原酶抑制剂，用于治疗高脂血症。我们的特点的影响，有机阴离子转运多肽1B 1（OATP 1B 1）等位基因 *1a，*1b，*15匹伐他汀的药代动力学。方法：24名健康韩国志愿者谁以前参加了匹伐他汀（单次口服剂量，1-8 mg）的药代动力学研究进行了进一步研究。根据OATP 1B 1基因型对受试者进行分组。分析了剂量标准化的血浆浓度-时间曲线下面积（AUC）和血浆峰浓度C-max值，因为受试者给药的剂量不同，而药代动力学呈线性特征。*1b/*1b（第1组）、*1a/*1a或 *1a/*1b（第2组）和 *1a/*15或 *1b/*15（第3组）的剂量标准化匹伐他汀AUC为38.8 +/- 13.3，54.4 +/- 12.4和68.1 +/- 16.3 ng中心点h中心点mL（-1）中心点mg（-1）（平均值+/- SD），所有3组之间（P =.008）以及携带和不携带 * 15等位基因的受试者之间（P =.004）存在显著差异。第1、2和3组中犬标准化匹伐他汀C-max值分别为13.2 +/- 3.3、18.2 +/- 5.7和29.4 +/- 9.6 ng中心点mL（-1）中心点mg（-1），也显示出与AUC相似的显著差异（P = 0.003）。在剂量标准化AUC或C-max方面，基因型组之间未发现显著差异。结论：OATP 1B 1变异单倍型对匹伐他汀的药代动力学有显著影响。这些结果表明，*15等位基因与匹伐他汀从血液进入肝细胞的摄取减少相关，OATP 1B 1基因多态性对匹伐他汀内酯的药代动力学无影响。
Background. Pitavastatin is a potent, newly developed 3-hydroxy-3-methylglutaryl- coenzyme A reductase inhibitor for the treatment of hyperlipidemia. We characterized the effects of organic anion transporting polypeptide 1B1 (OATP1B1) alleles *1a, *1b, and *15 on the pharmacokinetics of pitavastatin.Methods: Twenty-four healthy Korean volunteers who had-previously participated in a pharmacokinetic study of pitavastatin (single oral dose, 1-8 mg) were further investigated. Subjects were grouped according to OATP1B1 genotype. Dose-normalized area under the plasma concentration-time curve (AUC) and peak plasma concentration C-max values were analyzed, because different dosages were administered to subjects, whereas the pharmacokinetics showed linear characteristics.Results: Dose-normalized pitavastatin AUCs for *1b/*1b (group 1), *1a/*1a or *1a/*1b (group 2), and *1a/*15 or *1b/*15 (group 3) were 38.8 +/- 13.3, 54.4 +/- 12.4, and 68.1 +/- 16.3 ng center dot h center dot mL(-1) center dot mg(-1) (mean +/- SD), respectively, with significant differences between all 3 groups (P =.008) and between subjects carrying and those not carrying the * 15 allele (P =.004). Doge-normalized pitavastatin C-max values were 13.2 +/- 3.3, 18.2 +/- 5.7, and 29.4 +/- 9.6 ng center dot mL(-1) center dot mg(-1) in groups 1, 2, and 3, respectively, and also showed significant differences (P =.003) in a manner similar to that shown by AUC. No significant differences were found between the genotype groups in terms of dose-normalized AUC or C-max. values of pitavastatin lactone.Conclusion: OATP1B1 variant haplotypes were found to have a significant effect on the pharmacokinetics; of pitavastatin. These results suggest that the *15 allele is associated with decreased pitavastatin uptake from blood into hepatocytes and that OATP1B1 genetic polymorphisms have no effect on the pharmacokinetics of pitavastatin lactone.