Author(s): Mousa O, Brater DC, Sunblad KJ, Hall SD
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Abstract 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. 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 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. CONCLUSION: 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.
This article was published in Clin Pharmacol Ther
and referenced in Mass Spectrometry & Purification Techniques