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

https://doi.org/10.1016/j.cca.2009.04.003Get rights and content

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.

Introduction

Atorvastatin is one of the most potent 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors for treatment of hypercholesterolemia which is an important risk factor in the development of atherosclerosis and coronary heart disease (CHD). Several studies showed that organic anion transporting polypeptide 1B1 (OATP1B1) encoded by SLCO1B1 is specifically expressed at the basolateral membrane of hepatocytes and genetic variations in SLCO1B1 have been shown to impair the cellular uptake of its substrates including exogenous drugs and endogenous compounds [1], [2]. Naturally occurring SNP, SLCO1B1 521T>C (Val174Ala), was found to be associated with marked alterations of OATP1B1 transport activity in vitro [3]. It has been shown that the plasma concentration of pravastatin was 1.5-fold increased in subjects with SLCO1B1⁎5 haplotype compared with SLCO1B1⁎1a/⁎1a individuals [4]. Moreover, 2-fold higher blood concentration of simvastatin acid was observed in SLCO1B1 c.521CC individuals [5].

In human liver, atorvastatin undergoes extensive metabolism by cytochrome P450-3A4, which catalyzes 2 active metabolites, 2-hydroxy-atorvastatin acid and 4-hydroxyatorvastatin acid from the acid and the inactive lactone forms of atorvastatin [6], [7]. Inhibitors of CYP3A4, mibefradil, itraconazole and clarithromycin, markedly increased plasma exposure to atorvastatin in vivo [8]. Besides P450 enzymes, drug–drug interactions of atorvastatin are also reported at the level of hepatic transporters. Lau et al. found that rifampicin effectively decreased the hepatic uptake and efflux of atorvastatin by inhibiting the transport activity of Oatp and MRP2 in rats and OATP1B1 in humans [9], [10], [11]. Moreover, atorvastatin has been shown to be both a substrate and inhibitor of P-glycoprotein (P-gp) [12]. Being a probe drug of P-gp, digoxin plasma concentrations significantly increased when atorvastatin was co-administered [13].

Conflicting findings exist regarding the hepatic uptake of rifampicin. Tirona et al. demonstrated that OATP1B1 displayed far greater capability for rifampicin transport than OATP1B3 (also known as OATP8) in Hela cells [14]. However, Vavricka et al. found out that in Xenopus laevis oocytes expression system, OATP1B3 predominantly mediated the hepatic uptake of rifampicin and to a less extent by OATP1B1 [15]. The molecular base for rifampicin uptake from portal vein into hepatocytes in humans is not completely elucidated at present. However, common agreement exists that rifampicin is a potent blocker of OATP1B1 [14], [15], [16].

The primary goal of this study was to demonstrate if SLCO1B1 521T>C polymorphism had an impact on atorvastatin–rifampicin interaction in humans. The dependence of the plasma concentration of rifampicin and SLCO1B1 521T>C genotype was tested simultaneously.

Section snippets

Subjects

After genotyping a total of 111 unrelated Chinese healthy male volunteers aged 20 ± 2 y, 16 subjects were recruited in this study including 6 SLCO1B1 c.521TT, 6 c.521TC and 4 c.521CC subjects who did not differ significantly in age and body mass index as presented in Table 1. The genotyping analyses of SLCO1B1 521T>C were performed as described in our previous study [17]. Each participant's healthy status was determined by medical history, physical examination, routine blood and urine tests, and

Effect of SLCO1B1 521T>C polymorphism on the pharmacokinetics of rifampicin

As shown in Table 2 and Fig. 1, the AUC(0–∞) values of rifampicin were 61.6 ± 15.5 vs 57.0 ± 6.9 vs 58.9 ± 17.5 (P > 0.05) in participants with SLCO1B1 c.521TT, c.521TC and c.521CC genotypes. This showed that SLCO1B1 genotypes conferred no statistic impact on the pharmacokinetics of rifampicin.

Effect of rifampicin on atorvastatin kinetics based on SLCO1B1 521T>C genotype

Interestingly, SLCO1B1 521T>C significantly influenced the percentage of changes of atorvastatin pharmacokinetics. Among SLCO1B1 c.521TT, c.521TC and c.521CC groups the increase percentage of AUC(0–48) were 833 ± 

Discussion

In this study, we found that co-administration of rifampicin and atorvastatin may significantly change atorvastatin pharmacokinetics in vivo, while this effect could vary according to SLCO1B1 521T>C genotypes. Single oral dose of rifampicin significantly led to 5-fold increase of peripheral exposure of atorvastatin and the increase percentage of AUC(0–48) values were nearly tripled in SLCO1B1 c.521TT participants compared with c.521CC carriers.

OATP1B1 is specifically expressed at the

Acknowledgements

This work was supported by the National Natural Scientific Foundation of China grants F30130210, C30000211 and C30200346 and by China Medical Board of New York grants 99-697 and 01-755.

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