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1. Pharmacol Rep. 2011 Nov;63(6):1574-82.

Effects of simvastatin on the pharmacokinetics of diltiazem and its main
metabolite, desacetyldiltiazem, after oral and intravenous administration in
rats: possible role of P-glycoprotein and CYP3A4 inhibition by simvastatin.

Choi DH, Choi JS, Li C, Choi JS.

College of Medicine, Chosun University, Gwangju 501-759, Korea.

The purpose of this study was to investigate the possible effects of
hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor, simvastatin, on
the pharmacokinetics of diltiazem and its main metabolite, desacetyldiltiazem, in
rats. HMG-CoA reductase inhibitors and diltiazem are sometimes prescribed as a
combination therapy for the prevention or treatment of cardiovascular diseases.
The effect of simvastatin on P-glycoprotein (P-gp) and cytochrome P450 (CYP) 3A4
activity was evaluated. Simvastatin inhibited CYP3A4 enzyme activity in a
concentration-dependent manner with a 50% inhibition concentration (IC(50)) of
3.0 μM. In addition, simvastatin significantly enhanced the cellular accumulation
of rhodamine-123 in MCF-7/ADR cells overexpressing P-gp. The pharmacokinetic
parameters of diltiazem and desacetyldiltiazem were determined after oral and
intravenous administration of diltiazem to rats in the presence and absence of
simvastatin (0.3 and 1.0 mg/kg). The areas under the plasma concentration-time
curve (AUC) and the peak concentration (C(max)) of diltiazem were significantly
(p < 0.05, 1.0 mg/kg) increased by 45.2% and 35.2%, respectively, in the presence
of simvastatin compared to control. Consequently, the absolute bioavailability
(AB) values of diltiazem in the presence of simvastatin (1.0 mg/kg) were
significantly (p < 0.05) higher (44.8%) than that of the control group. Moreover,
the relative bioavailability (RB) of diltiazem was 1.21- to 1.45-fold greater
than that in the control group. The metabolite-parent AUC ratio (MR) in the
presence of simvastatin (1.0 mg/kg) significantly decreased compared to the
control group. This result implied that simvastatin effectively inhibited the
metabolism of diltiazem. The increase in diltiazem oral bioavailability might be
attributable to enhanced absorption in the small intestine via the inhibition of
P-gp and to reduced first-pass metabolism of diltiazem via the inhibition of the
CYP3A subfamily in the small intestine and/or in the liver rather than renal
elimination of diltiazem by simvastatin.

PMID: 22358108 [PubMed - in process]