Background: Rifampin (rifampicin) is a potent inducer of several cytochrome
P450 (CYP) enzymes, including CYP3A4, The cholesterol-lowering drug simvas
tatin has an extensive first-pass metabolism, and it is partially metaboliz
ed by CYP3A4, This study was conducted to investigate the effect of rifampi
n 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 m
etabolite simvastatin acid were measured up to 12 hours with a sensitive li
quid chromatography-ion spray tandem mass spectrometry method.
Results: Rifampin decreased the total area under the plasma concentration-t
ime 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 simvas
tatin and simvastatin acid. Because the elimination half-life of simvastati
n 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.