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 cholesterol-lowering efficacy of simvastatin.
Kyrklund
C
C
Department of Clinical Pharmacology, University of Helsinki and Helsinki University Central Hospital, Finland.
Backman
J T
JT
Kivistö
K T
KT
Neuvonen
M
M
Laitila
J
J
Neuvonen
P J
PJ
D000328:Adult; D000904:Antibiotics, Antitubercular / Q000494:pharmacology*; D000924:Anticholesteremic Agents / Q000097:blood* / Q000493:pharmacokinetics; D019540:Area Under Curve; D018592:Cross-Over Studies; D004347:Drug Interactions; D006801:Humans; D008297:Male; D012293:Rifampin / Q000494:pharmacology*; D019821:Simvastatin / Q000031:analogs & derivatives* / Q000097:blood* / Q000493:pharmacokinetics
D000904:Antibiotics, Antitubercular; D000924:Anticholesteremic Agents; C063287:simvastatin acid; D019821:Simvastatin; D012293:Rifampin