Effects of a concomitant single oral dose of rifampicin on the pharmacokinetics of pravastatin in a two-phase, randomized, single-blind, placebo-controlled, crossover study in healthy Chinese male subjects.
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): C(max) (315.7 [227.2] and 115.8 [77.5] ng . mL(-1) [P = 0.009]); AUC(0-12) (604.8 [73.3] and 259.0 [133.4] ng . h . mL(-1) [P < 0.001]); AUC(0-infinity)) (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 T(max) or t((1/2)) 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.


CONCLUSIONS
Coadministration of a single oral dose of rifampicin significantly increased the plasma concentration of pravastatin in this group of healthy Chinese male subjects.
Deng
Sheng
S
Department of Pharmacy, Xiangya Hospital, Central South University, Changsha, People's Republic of China.
Chen
Xiao-Ping
XP
Cao
Dan
D
Yin
Tao
T
Dai
Zhi-Yong
ZY
Luo
Jian
J
Tang
Ling
L
Li
Yuan-Jian
YJ
D000293:Adolescent; D000328:Adult; D000904:Antibiotics, Antitubercular / Q000494:pharmacology*; D000924:Anticholesteremic Agents / Q000009:adverse effects / Q000493:pharmacokinetics*; D019540:Area Under Curve; D002681:China; D002851:Chromatography, High Pressure Liquid; D018592:Cross-Over Studies; D004347:Drug Interactions; D006207:Half-Life; D006801:Humans; D008297:Male; D017035:Pravastatin / Q000009:adverse effects / Q000493:pharmacokinetics*; D012293:Rifampin / Q000494:pharmacology*; D016037:Single-Blind Method; D053719:Tandem Mass Spectrometry; D055815:Young Adult
D000904:Antibiotics, Antitubercular; D000924:Anticholesteremic Agents; D017035:Pravastatin; D012293:Rifampin