The interaction of diltiazem with simvastatin.
BACKGROUND
Simvastatin is an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase that is used as a cholesterol-lowering agent and is metabolized by cytochrome P450 3A (CYP3A) enzymes. Diltiazem is a substrate and an inhibitor of CYP3A enzymes and is commonly coadministered with cholesterol-lowering agents such as simvastatin. The objective of this study was to quantify the effect of diltiazem on the pharmacokinetics of simvastatin.


METHODS
A fixed-order study was conducted in 10 healthy volunteers with a 2-week washout period between the phases. In one arm of the study, a single 20-mg dose of simvastatin was administered orally; the second arm entailed administration of a single 20-mg dose of simvastatin orally after 2 weeks of treatment with 120 mg diltiazem twice a day.


RESULTS
Diltiazem significantly increased the mean peak serum concentration of simvastatin by 3.6-fold (P < .05) and simvastatin acid by 3.7-fold (P < .05). Diltiazem also significantly increased the area under the serum concentration-time curve of simvastatin 5-fold (P < .05) and the elimination half-life 2.3-fold (P < .05). There was no change in the time to peak concentration for simvastatin and simvastatin acid.


CONCLUSIONS
Diltiazem coadministration resulted in a significant interaction with simvastatin, probably by inhibiting CYP3A-mediated metabolism. Concomitant use of diltiazem or other potent inhibitors of CYP3A with simvastatin should be avoided, or close clinical monitoring should be used.
Mousa
O
O
Department of Medicine, Indiana University School of Medicine, Indianapolis, USA.
Brater
D C
DC
Sunblad
K J
KJ
Hall
S D
SD
D000328:Adult; D002317:Cardiovascular Agents / Q000008:administration & dosage / Q000494:pharmacology*; D004110:Diltiazem / Q000008:administration & dosage / Q000494:pharmacology*; D004334:Drug Administration Schedule; D004347:Drug Interactions; D005260:Female; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D008297:Male; D012016:Reference Values; D019821:Simvastatin / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*
D002317:Cardiovascular Agents; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D019821:Simvastatin; D004110:Diltiazem