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Abstract: Background: Pravastatin is a potent cholesterol-lowering agent; ~34% of an oral dose of pravastatin is eliminated unchanged through biliary and urinary excretion. Rifampicin is an inducer of drug metabolism enzymes, and it affects the activities of transporters involved in pravastatin disposition. Drug-drug interaction between rifampicin and pravastatin is possible because of the effects of rifampicin on the activities of drug transporters. Objective: This study was designed to investigate the effects of a single oral dose of rifampicin on the pharmacokinetics of pravastatin. Methods: Healthy Chinese male volunteers were recruited for this 2-phase, single-blind, placebo-controlled, crossover study. The subjects were randomly divided into 2 groups to receive either rifam-picin or placebo concomitantly with pravastatin. All subjects received a 20-mg oral dose of pravastatin on days 1 and 9, separated by an 8-day washout period. Subjects in the rifampicin group received a single 600-mg oral dose of rifampicin on day 1 and placebo on day 9; those in the placebo group received placebo on day 1 and a single 600-mg oral dose of rifampicin on day 9. High-performance liquid chromatography-tandem mass spectrometry was used to determine plasma concentrations of pravastatin for up to 12 hours after administration. Results: Twelve volunteers participated in the study (6 per group). The mean (SD) age of the subjects was 20 (2) years (range, 18–25 years). The mean height of the subjects was 174 (4) cm (range, 168–180 cm), and the mean weight was 69.2 (3.7) kg (range, 65–77 kg). The mean pharmacokinetic parameters for pravastatin that changed significantly were as follows (rifampicin and placebo groups, respectively): Cmax (315.7 [227.2] and 115.8 [77.5] ng · mL−1 [P = 0.009]); AUC0–12 (604.8 [73.3] and 259.0 [133.4] ng · h · mL−1 [P < 0.001]); AUC0–∞) (623.3 [248.8] and 275.1 [58.5] ng · h · mL−1 [P < 0.001]); and apparent oral clearance (CL/F) (0.52 [0.18] and 1.30 [0.58] L · h−1 · kg−1 [P < 0.001]). No significant changes in the Tmax or t½ of pravastatin were observed. All subjects tolerated pravastatin well during both phases of the study, with or without coadministration of rifampicin. None of the subjects withdrew from the study. Conclusion: Coadministration of a single oral dose of rifampicin significantly increased the plasma concentration of pravastatin in this group of healthy Chinese male subjects. [Copyright &y& Elsevier]

1. Pravastatin is a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor used for the treatment of hyperlipidaemia. This study aims to investigate the effects of genetic polymorphisms in OATP1B1, BCRP and NTCP on pravastatin population pharmacokinetics in healthy Chinese volunteers using a non-linear mixed-effect modelling (NONMEM) approach. A two-compartment model with a first-order absorption and elimination described plasma pravastatin concentrations well. 2. Genetic polymorphisms of rs4149056 (OATP1B1) and rs2306283 (OATP1B1) were found to be associated with a significant (p < 0.01) decrease in the apparent clearance from the central compartment (CL/F), while rs2296651 (NTCP) increased CL/F to a significant degree (p < 0.01). The combination of these three polymorphisms reduced the inter-individual variability of CL/F by 78.8%. 3. There was minimal effect of rs2231137 (BCRP) and rs2231142 (BCRP) on pravastatin pharmacokinetics (0.01 < p < 0.05), whereas rs11045819 (OATP1B1), rs1061018 (BCRP) and rs61745930 (NTCP) genotypes do not appear to be associated with pravastatin pharmacokinetics based on the population model (p > 0.05). 4. The current data suggest that the combination of rs4149056, rs2306283 and rs2296651 polymorphisms is an important determinant of pravastatin pharmacokinetics.