Background: Simvastatin is an inhibitor of 3-hydroxy-3-methylglutaryl coenz
yme A (HMG-CoA) reductase that is used as a cholesterol-lowering agent and
is metabolized by cytochrome P450 3A (CYP3A) enzymes. Diltiazem is a substr
ate and an inhibitor of CYP3A enzymes and is commonly coadministered with c
holesterol-lowering agents such as simvastatin, The objective of this study
was to quantify the effect of diltiazem on the pharmacokinetics of simvast
atin.
Method: 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 o
f treatment with 120 mg diltiazem twice a day.
Results: Diltiazem significantly increased the mean peak serum concentratio
n 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 con
centration-time curve of simvastatin fi-fold (P <.05) and the elimination h
alf-life 2.3-fold (P < .05), There was no change in the time to peak concen
tration for simvastatin and simvastatin acid.
Conclusion: Diltiazem coadministration resulted in a significant interactio
n with simvastatin, probably by inhibiting CYP3A-mediated metabolism, Conco
mitant use of diltiazem or other potent inhibitors of CYP3A with simvastati
n should be avoided, or close clinical monitoring should be used.