Rifampin greatly reduces plasma simvastatin and simvastatin acid concentrations

Background Rifampin (rifampicin) is a potent inducer of several cytochrome P450 (CYP) enzymes, including CYP3A4. The cholesterol‐lowering drug simvastatin has an extensive first‐pass metabolism, and it is partially metabolized by CYP3A4. This study was conducted to investigate the effect of rifampin on the pharmacokinetics of simvastatin. Methods In a randomized cross‐over study with two phases and a washout of 4 weeks, 10 healthy volunteers received a 5‐day pretreatment with rifampin (600 mg daily) or placebo. On day 6, a single 40‐mg dose of simvastatin was administered orally. Plasma concentrations of simvastatin and its active metabolite simvastatin acid were measured up to 12 hours with a sensitive liquid chromatography‐ion spray tandem mass spectrometry method. Results Rifampin decreased the total area under the plasma concentration‐time curve of simvastatin and simvastatin acid by 87% (P < .001) and 93% (P < .001), respectively. Also the peak concentrations of both simvastatin and simvastatin acid were reduced greatly (by 90%) by rifampin (P < .001). On the other hand, rifampin had no significant effect on the elimination half‐life of simvastatin or simvastatin acid. Conclusions Rifampin greatly decreases the plasma concentrations of simvastatin and simvastatin acid. Because the elimination half‐life of simvastatin was not affected by rifampin, induction of the CYP3A4‐mediated first‐pass metabolism of simvastatin in the intestine and the liver probably explains this interaction. Concomitant use of potent inducers of CYP3A4 can lead to a considerably reduced cholesterollowering efficacy of simvastatin. Clinical Pharmacology & Therapeutics (2000) 68, 592–597; doi: 10.1067/mcp.2000.111414