Evidence for inverse effects of OATP-C (SLC21A6) *5 and *1b haplotypes on pravastatin kinetics
Evidence for inverse effects of OATP-C (SLC21A6) *5 and *1b haplotypes on pravastatin kinetics
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DOI：
10.1016/j.clpt.2003.12.016
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发表时间：
2004-05-01
影响因子：
6.7
通讯作者：
Gerloff, T
中科院分区：
文献类型：
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作者：
Mwinyi, J;Johne, A;Gerloff, T
目的：我们比较了OATP-C（有机阴离子转运多肽C）*1a，*1b（A388 G）和 *5（T521 C）单倍型对普伐他汀在白色subjects.Methods单剂量药代动力学的药物遗传学效应：30名健康白色男性受试者根据他们的OATP-Chaplotype进行分组。每组包含10个个体，他们是 *1a、*1b或 *5单倍型的纯合或杂合携带者。结果：*1a/*1a、*1a/*1bor *1b/*1b和 *1a/* 5个体0 - 6小时血浆浓度-时间曲线下面积[AUC（0-6）]为114.5 +/- 68.6 mug-L-1。h，74.8 ± 35.6 μ g。L-1. h和163.0 ± 64.6 μ g. L-1. h，在所有3个研究组之间（P = 0.006）以及携带 *1b和 *5单倍型的受试者之间（P = 0.002）具有高度显著性差异。值得注意的是，OATP-C *1b组的AUC（0-6）值比野生型OATP-C *1a单倍型携带者的AUC（0 - 6）值低60%以上，尽管该差异未达到统计学显著性。然而，在OATP-C *1b单倍型组中，从时间0到12小时[Ae（0-12）]排泄到尿液中的普伐他汀量显著减少（1729 t 907 p，g）与 *1a野生型对照受试者相比（2974 +/- 1590 mug）（P = 0.049）。结论：受试OATP-C变异单倍型对普伐他汀处置有显著影响。而 *5表达延迟了肝细胞对普伐他汀的摄取，*1b表达似乎加速了药物的OATP-C依赖性摄取。
Objective: We compared the pharmacogenetic effects of OATP-C (organic anion transporting polypeptide C) *1a, *1b (A388G), and *5 (T521C) haplotypes on single-dose pharmacokinetics of pravastatin in white subjects.Methods: Thirty healthy white male subjects were grouped according to their OATP-Chaplotype. Each group contained 10 individuals who were either homozygous or heterozygous carriers of the *1a, *1b, or *5 haplotype. After a single oral dose of 40 mg pravastatin, we analyzed kinetic parameters of pravastatin disposition.Results: Values for the area under the plasma concentration-time curve from time 0 to 6 hours [AUC(0-6)] in *1a/*1a, *1a/*1bor *1b/*1b, and *1a/*5individuals were 114.5 +/- 68.6 mug - L-1. h, 74.8 +/- 35.6 mug . L-1. h, and 163.0 +/- 64.6 mug. L-1. h, respectively, with highly significant differences across all 3 study groups (P =.006) and between subjects carrying the *1b and *5 haplotype (P =.002). Strikingly, values of AUC(0-6) from the OATP-C *1b group were more than 60% lower than those derived from carriers of the wild-type OATP-C *1a haplotype, although this difference failed to reach statistical significance. However, the amount of pravastatin excreted into the urine from time 0 to 12 hours [Ae(0-12)] was significantly diminished in the OATP-C *1b haplotype group (1729 t 907 p,g) compared with *1a wild-type control subjects (2974 +/- 1590 mug) (P =.049).Conclusion: There was a significant effect of tested OATP-C variant haplotypes on pravastatin disposition. Whereas *5 expression delayed the hepatocellular uptake of pravastatin, *1b expression seemed to accelerate OATP-C-dependent uptake of the drug.