Effect of OATP1B transporter inhibition on the pharmacokinetics of atorvastatin in healthy volunteers
Effect of OATP1B transporter inhibition on the pharmacokinetics of atorvastatin in healthy volunteers
复制标题
DOI：
10.1038/sj.clpt.6100038
复制
发表时间：
2007-02-01
影响因子：
6.7
通讯作者：
Benet, L. Z.
中科院分区：
文献类型：
--
作者：
Lau, Y. Y.;Huang, Y.;Benet, L. Z.
肝摄取转运体，如OATP1B1，对阿托伐他汀药代动力学的抑制作用尚不清楚。在这里，我们研究了一种模型肝转运蛋白抑制剂利福平对阿托伐他汀及其代谢物在人体内动力学的影响。采用随机、交叉研究方法，研究了11名健康志愿者单剂量利福平对阿托伐他汀动力学的抑制作用。每个受试者接受两次40毫克的阿托伐他汀治疗，一次在研究第1天，另一次在研究第8天，间隔1周。在研究第1天或第8天，每个受试者静脉滴注利福平600 mg，每次30min。阿托伐他汀及其代谢物的血浆浓度在给药后24小时内均超过定量限值。利福平显著增加阿托伐他汀酸的血药浓度-时间曲线下总面积(AUC)6.8+/-2.4倍，2-羟基-阿托伐他汀酸和4-羟基-阿托伐他汀酸分别增加6.8+/-2.5倍和3.9+/-2.4倍。内酯形式的阿托伐他汀、2-羟基-阿托伐他汀和4-羟基-阿托伐他汀的AUC值也显著增加，但幅度较小。静脉注射利福平可显著增加阿托伐他汀及其酸和内酯代谢物的血浆浓度。这些数据证实了OATP1B转运体是阿托伐他汀及其活性代谢物的主要肝脏摄取系统。抑制肝脏摄取可能会影响阿托伐他汀等药物的疗效和毒性，阿托伐他汀主要由肝胆系统消除。
The inhibition of hepatic uptake transporters, such as OATP1B1, on the pharmacokinetics of atorvastatin is unknown. Here, we investigate the effect of a model hepatic transporter inhibitor, rifampin, on the kinetics of atorvastatin and its metabolites in humans. The inhibitory effect of a single rifampin dose on atorvastatin kinetics was studied in 11 healthy volunteers in a randomized, crossover study. Each subject received two 40-mg doses of atorvastatin, one on study day 1 and one on study day 8, separated by 1 week. One intravenous 30-min infusion of 600 mg rifampin was administered to each subject on either study day 1 or study day 8. Plasma concentrations of atorvastatin and metabolites were above the limits of quantitation for up to 24 h after dosing. Rifampin significantly increased the total area under the plasma concentration-time curve (AUC) of atorvastatin acid by 6.8 +/- 2.4-fold and that of 2-hydroxy-atorvastatin acid and 4-hydroxy-atorvastatin acid by 6.8 +/- 2.5- and 3.9 +/- 2.4-fold, respectively. The AUC values of the lactone forms of atorvastatin, 2-hydroxy-atorvastatin and 4-hydroxy-atorvastatin, were also significantly increased, but to a lower extent. An intravenous dose of rifampin substantially increased the plasma concentrations of atorvastatin and its acid and lactone metabolites. The data confirm that OATP1B transporters represent the major hepatic uptake systems for atorvastatin and its active metabolites. Inhibition of hepatic uptake may have consequences for efficacy and toxicity of drugs like atorvastatin that are mainly eliminated by the hepatobiliary system.