Effect of OATP1B Transporter Inhibition on the Pharmacokinetics of Atorvastatin in Healthy Volunteers

Abstract

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.

Function-impairing polymorphisms of the hepatic uptake transporter SLCO1B1 modify the therapeutic efficacy of statins in a population-based cohort

“…As mentioned before, statin therapy is accepted widely as an important strategy to reduce cardiovascular incidences; assuming that the OATP1B1 genotype is predictive for the efficacy of this treatment would suggest that genotyping before starting treatment could be a useful tool to stratify patients at risk. Surprisingly, our data indicate that patients treated with atorvastatin, even if characterized as a substrate of OATP1B1 [28,29], did not show a predictive value of the SLCO1B1 genotype on drug efficacy or treatment outcome. This is in accordance with the findings obtained by Thompson et al [6], who carried out a genome-wide association study that sought markers predictive for LDL-cholesterol reduction in a population summarizing For analysis of the summarized statin group, the simvastatin equipotent dose was used.…”

Metabolism and Toxicity of Drugs. Two Decades of Progress in Industrial Drug Metabolism

“…A case in point is the antihypercholesterolemic agent atorvastatin, which, along with active hydroxylated metabolites that are formed by CYP3A4, is actively taken up into liver tissue by organic ion-transporting polypeptides (OATPs) such as OATP1B1. Rifampicin has been shown to inhibit these transporters (14) such that when atorvastatin is dosed together with rifampicin, a significant increase in systemic exposure to both atorvastatin and its metabolites results (15).…”

An updated review of interactions of statins with antibacterial and antifungal agents

“…One dose of concomitant rifampin resulted in an increase in the AUC of atorvastatin, pitavastatin, and pravastatin by 7 times, 5.8 times, and 2.3 times their original values, respectively [26][27][28]. This effect can be explained by rapid OATP1B1/3 inhibition by rifampin [26]. In contrast, 5 days of rifampin nonsimultaneous administration resulted in an 80% decrease in the AUC of atorvastatin [29].…”

“…The interaction of atorvastatin with rifampin is interesting because it is time-dependent and caused by a dual interaction mechanism. One dose of concomitant rifampin resulted in an increase in the AUC of atorvastatin, pitavastatin, and pravastatin by 7 times, 5.8 times, and 2.3 times their original values, respectively [26][27][28]. This effect can be explained by rapid OATP1B1/3 inhibition by rifampin [26].…”

“…For daptomycin, systematic and manual searches identified four PK studies [21][22][23][24] and one [25] observational study, respectively. For rifampin, a systematic search identified three PK studies [26][27][28] assessing the impact of single dose and four PK studies [29][30][31][32] assessing the impact of multiple doses. Eight [33][34][35][36][37][38][39][40] PK studies were identified for azole antifungals.…”