Effects of lovastatin on the pharmacokinetics of diltiazem and its main metabolite, desacetyldiltiazem, in rats: possible role of cytochrome P450 3A4 and P-glycoprotein inhibition by lovastatin.

OBJECTIVES

The purpose of this study was to examine the effects of lovastatin on cytochrome P450 (CYP) 3A4 and P-glycoprotein (P-gp) in vitro and then to determine the effects of lovastatin on the pharmacokinetics of diltiazem and its main metabolite, desacetyldiltiazem, in rats.

METHODS

The pharmacokinetic parameters of diltiazem and desacetyldiltiazem were determined after orally administering diltiazem (12 mg/kg) to rats in the presence and absence of lovastatin (0.3 and 1.0 mg/kg). The effect of lovastatin on P-gp as well as CYP3A4 activity was also evaluated.

KEY FINDINGS

Lovastatin inhibited CYP3A4 enzyme activity with a 50% inhibition concentration of 6.06 µM. In addition, lovastatin significantly enhanced the cellular accumulation of rhodamine-123 in MCF-7/ADR cells overexpressing P-gp. Compared with the control (given diltiazem alone), the presence of lovastatin significantly altered the pharmacokinetic parameters of diltiazem. The areas under the plasma concentration-time curve (AUC) and the peak concentration of diltiazem were significantly increased (P < 0.05, 1.0 mg/kg) in the presence of lovastatin. Consequently, the absolute bioavailability values of diltiazem in the presence of lovastatin (11.1% at 1.0 mg/kg) were significantly higher (P < 0.05) than that of the control group (7.6%). The metabolite-parent AUC ratio in the presence of lovastatin (1.0 mg/kg) was significantly (P < 0.05) decreased compared with the control group.

CONCLUSIONS

It might be considered that lovastatin resulted in reducing the first-pass metabolism in the intestine and/or in the liver via inhibition of CYP3A4 and increasing the absorption of diltiazem in the intestine via inhibition of P-gp by lovastatin.