Rifampin greatly reduces plasma simvastatin and simvastatin acid concentrations

Clin Pharmacol Ther. 2000 Dec;68(6):592-7. doi: 10.1067/mcp.2000.111414.


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 cholesterol-lowering efficacy of simvastatin.

Publication types

  • Clinical Trial
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Antibiotics, Antitubercular / pharmacology*
  • Anticholesteremic Agents / blood*
  • Anticholesteremic Agents / pharmacokinetics
  • Area Under Curve
  • Cross-Over Studies
  • Drug Interactions
  • Humans
  • Male
  • Rifampin / pharmacology*
  • Simvastatin / analogs & derivatives*
  • Simvastatin / blood*
  • Simvastatin / pharmacokinetics


  • Antibiotics, Antitubercular
  • Anticholesteremic Agents
  • simvastatin acid
  • Simvastatin
  • Rifampin