利福平基于SLCO1B1基因521T>C多态性改变阿托伐他汀的血浆浓度。

Rifampicin alters atorvastatin plasma concentration on the basis of SLCO1B1 521T>C polymorphism.

作者信息

He Yi-Jing, Zhang Wei, Chen Yao, Guo Dong, Tu Jiang-Hua, Xu Lin-Yong, Tan Zhi-Rong, Chen Bi-Lian, Li Zhi, Zhou Gan, Yu Bang-Ning, Kirchheiner Julia, Zhou Hong-Hao

机构信息

Pharmacogenetics Research Institute, Institute of Clinical Pharmacology, Central South University, Changsha, Hunan, 410078, China.

出版信息

Clin Chim Acta. 2009 Jul;405(1-2):49-52. doi: 10.1016/j.cca.2009.04.003. Epub 2009 Apr 14.

DOI:10.1016/j.cca.2009.04.003

PMID:19374892

Abstract

BACKGROUND

Both atorvastatin and rifampicin are substrates of OATP1B1 (organic anion transporting polypeptide 1B1) encoded by SLCO1B1 gene. Rifampicin is a potent inhibitor of SLCO1B1 (IC50 1.5 umol/l) and SLCO1B1 521T>C functional genetic polymorphism alters the kinetics of atorvastatin in vivo. We hypothesize that rifampicin might influence atorvastatin kinetics in a SLCO1B1 polymorphism dependent manner.

METHODS

Sixteen subjects with known SLCO1B1 genotypes (6 c.521TT, 6 c.521TC and 4 c.521CC) were divided into 2 groups (atorvastatin-placebo group, n=8; atorvastatin-rifampicin group, n=8) randomly. In this 2-phase crossover study, atorvastatin (40 mg single-oral dose) pharmacokinetics after co-administration of placebo and rifampicin (600 mg single-oral dose) were measured for up to 48 h by liquid chromatography-mass spectrometry (LC-MS). In the third phase, rifampicin (450 mg single-oral dose) pharmacokinetics was measured additionally.

RESULTS

Rifampicin increased atorvastatin plasma concentration in accordance with SLCO1B1 521T>C genotype while the increasing percentage of AUC((0-48)) among c.521TT, c.521TC and c.521CC individuals were 833+/-245% vs 468+/-233% vs 330+/-223% (P=0.007). However, SLCO1B1 521T>C exerted no impact on rifampicin pharmacokinetics (P>0.05).

CONCLUSIONS

These results suggested that rifampicin elevated the plasma concentration of atorvastatin depending on SLCO1B1 genotype and rifampicin pharmacokinetics were not altered by SLCO1B1 genotype.

摘要

背景

阿托伐他汀和利福平均为SLCO1B1基因编码的有机阴离子转运多肽1B1（OATP1B1）的底物。利福平是SLCO1B1的强效抑制剂（IC50为1.5 μmol/l），且SLCO1B1 521T>C功能基因多态性会改变阿托伐他汀的体内动力学。我们推测利福平可能以依赖SLCO1B1多态性的方式影响阿托伐他汀的动力学。

方法

16名已知SLCO1B1基因型的受试者（6名c.521TT、6名c.521TC和4名c.521CC）被随机分为2组（阿托伐他汀-安慰剂组，n = 8；阿托伐他汀-利福平组，n = 8）。在这项两阶段交叉研究中，通过液相色谱-质谱联用（LC-MS）测定了在服用安慰剂和利福平（单次口服剂量600 mg）后，阿托伐他汀（单次口服剂量40 mg）长达48小时的药代动力学。在第三阶段，额外测定了利福平（单次口服剂量450 mg）的药代动力学。

结果

利福平根据SLCO1B1 521T>C基因型增加了阿托伐他汀的血浆浓度，而c.521TT、c.521TC和c.521CC个体中AUC((0 - 48))的增加百分比分别为833±245% vs 468±233% vs 330±223%（P = 0.007）。然而，SLCO1B1 521T>C对利福平的药代动力学没有影响（P>0.05）。