Rifampicin alters atorvastatin plasma concentration on the basis of SLCO1B1 521T>C polymorphism
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.
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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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2019, Drug Metabolism and PharmacokineticsCitation Excerpt :Conversely, many clinical reports indicated that plasma concentration of multiple OATP1B1 substrate drugs in subjects with SLCO1B1 c.521T>C was significantly increased compared with that in subjects with wild-type allele [35]. In the case of atorvastatin, it was reported that healthy subjects with SLCO1B1 c.521TC and c.521CC showed increased plasma AUCs by 15–80% and 67–145%, respectively compared with that in subjects with c.521TT [21–24]. In our current study, the plasma AUC of atorvastatin in the hypercholesterolemic patients with SLCO1B1 c.521TC and c.521CC increased by 39% and 101%, respectively, compared with that in patients with c.521TT following the oral administration of therapeutic dose.
Quantitative Analysis of the Transporter-Mediated Drug-Drug Interaction Between Atorvastatin and Rifampicin Using a Stable Isotope-IV Method
2017, Journal of Pharmaceutical SciencesCitation Excerpt :Among the clinically important drug transporters defined in US Food and Drug Administration guidance, OATP1B1 is known to mediate the hepatic uptake of HMG-CoA reductase inhibitors, including pravastatin, rosuvastatin, and atorvastatin (ATV).6 Inhibition of OATP1B1 by coadministration of cyclosporine or rifampin (single dose) was reported to increase the systemic exposure of those statins significantly due to the decrease in their hepatic uptake, leading to the high risk of rhabdomyolysis.7-9 In this study, the DDI between ATV and rifampicin (RIF) was investigated by the isotope-IV method using a deuterium-labeled atorvastatin as a stable isotope.