Maeda Kazuya, Ieiri Ichiro, Yasuda Kuninobu, Fujino Akiharu, Fujiwara Hiroaki, Otsubo Kenji, Hirano Masaru, Watanabe Takao, Kitamura Yoshiaki, Kusuhara Hiroyuki, Sugiyama Yuichi
Department of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo, Tokyo, Japan.
Clin Pharmacol Ther. 2006 May;79(5):427-39. doi: 10.1016/j.clpt.2006.01.011. Epub 2006 Apr 11.
Recent reports have shown that genetic polymorphisms in organic anion transporting polypeptide (OATP) 1B1 have an effect on the pharmacokinetics of drugs. However, the impact of OATP1B11b alleles, the frequency of which is high in all ethnicities, on the pharmacokinetics of substrate drugs is not known after complete separation of subjects with OATP1B11a and *1b. Furthermore, the correlation between the clearances of OATP1B1 substrate drugs in individuals has not been characterized. We investigated the effect of genetic polymorphism of OATP1B1, particularly the *1b allele, on the pharmacokinetics of 3 anionic drugs, pravastatin, valsartan, and temocapril, in Japanese subjects.
Twenty-three healthy Japanese volunteers were enrolled in a 3-period crossover study. In each period, after a single oral administration of pravastatin, valsartan, or temocapril, plasma and urine were collected for up to 24 hours.
The area under the plasma concentration-time curve (AUC) of pravastatin in *1b/*1b carriers (47.4 +/- 19.9 ng.h/mL) was 65% of that in *1a/*1a carriers (73.2 +/- 23.5 ng.h/mL) (P = .049). Carriers of *1b/*15 (38.2 +/- 15.9 ng.h/mL) exhibited a 45% lower AUC than *1a/*15 carriers (69.2 +/- 23.4 ng.h/mL) (P = .024). In the case of valsartan we observed a similar trend as with pravastatin, although the difference was not statistically significant (9.01 +/- 3.33 microg.h/mL for *1b/*1b carriers versus 12.3 +/- 4.6 microg.h/mL for *1a/*1a carriers [P = .171] and 6.31 +/- 3.64 microg.h/mL for *1b/*15 carriers versus 9.40 +/- 4.34 microg.h/mL for *1a/*15 carriers [P = .213]). The AUC of temocapril also showed a similar trend (12.4 +/- 4.1 ng.h/mL for *1b/*1b carriers versus 18.5 +/- 7.7 ng.h/mL for *1a/*1a carriers [P = .061] and 16.4 +/- 5.0 ng.h/mL for *1b/*15 carriers versus 19.0 +/- 4.1 ng.h/mL for *1a/*15 carriers [P = .425]), whereas that of temocaprilat (active form of temocapril) was not significantly affected by the haplotype of OATP1B1. Interestingly, the AUC of valsartan and temocapril in each subject was significantly correlated with that of pravastatin (R = 0.630 and 0.602, P < .01). The renal clearance remained unchanged for each haplotype for all drugs.
The major clearance mechanism of pravastatin, valsartan, and temocapril appears to be similar, and OATP1B1*1b is one of the determinant factors governing the interindividual variability in the pharmacokinetics of pravastatin and, possibly, valsartan and temocapril.
近期报告显示，有机阴离子转运多肽（OATP）1B1的基因多态性对药物的药代动力学有影响。然而，在将携带OATP1B11a和1b的受试者完全区分开后，OATP1B11b等位基因（在所有种族中频率都很高）对底物药物药代动力学的影响尚不清楚。此外，个体中OATP1B1底物药物清除率之间的相关性也未得到明确。我们研究了OATP1B1基因多态性，特别是1b等位基因，对3种阴离子药物（普伐他汀、缬沙坦和替莫卡普利）在日本受试者中药代动力学的影响。
23名健康的日本志愿者参与了一项3期交叉研究。在每个阶段，单次口服普伐他汀、缬沙坦或替莫卡普利后，收集长达24小时的血浆和尿液。
*1b/1b携带者中普伐他汀的血浆浓度-时间曲线下面积（AUC）（47.4±19.9 ng·h/mL）是1a/*1a携带者（73.2±23.5 ng·h/mL）的65%（P = 0.049）。*1b/15携带者（38.2±15.9 ng·h/mL）的AUC比1a/*15携带者（69.2±23.4 ng·h/mL）低45%（P = 0.024）。对于缬沙坦，我们观察到与普伐他汀类似的趋势，尽管差异无统计学意义（*1b/*1b携带者为9.01±3.33 μg·h/mL，*1a/*1a携带者为12.3±4.6 μg·h/mL [P = 0.171]；*1b/*15携带者为6.31±3.64 μg·h/mL，*1a/*15携带者为9.40±4.34 μg·h/mL [P = 0.213]）。替莫卡普利的AUC也显示出类似趋势（*1b/*1b携带者为12.4±4.1 ng·h/mL，*1a/*1a携带者为18.5±7.7 ng·h/mL [P = 0.061]；*1b/*15携带者为16.4±5.0 ng·h/mL，*1a/*15携带者为19.0±4.1 ng·h/mL [P = 0.425]），而替莫卡普利拉（替莫卡普利的活性形式）的AUC不受OATP1B1单倍型的显著影响。有趣的是，每个受试者中缬沙坦和替莫卡普利的AUC与普伐他汀的AUC显著相关（R = 0.630和0.602，P < 0.01）。所有药物每种单倍型的肾脏清除率均保持不变。
普伐他汀、缬沙坦和替莫卡普利的主要清除机制似乎相似，OATP1B1*1b是决定普伐他汀以及可能的缬沙坦和替莫卡普利药代动力学个体间差异的因素之一。
