effect of atorvastatin on the pharmacokinetics of diltiazem and its main metabolite, desacetyldiltiazem, in rats

Abstract

The purpose of this study was to investigate the effect of atorvastatin, HMG-CoA reductase inhibitor, on the pharmacokinetics of diltiazem and its active metabolite, desacetyldiltiazem, in rats. Pharmacokinetic parameters of diltiazem and desacetyldiltiazem were determined in rats after oral administration of diltiazem (15 mg x kg(-1)) to rats pretreated with atorvastatin (0.5 or 2.0 mg x kg(-1)). Compared with the control (given diltiazem alone), the pretreatment of atorvastatin significantly altered the pharmacokinetic parameters of diltiazem. The peak concentration (Cmax) and the areas under the plasma concentration-time curve (AUC) of diltiazem were significantly (p < 0.05, 0.5 mg x kg(-1); p < 0.01, 2.0 mg x kg(-1)) increased in the presence of atorvastatin. The AUC of diltiazem was increased by 1.40-fold in rats pretreated with 0.5 mg x kg(-1) atorvastatin, and 1.77-fold in rats pretreated with 2.0 mg x kg(-1) atorvastatin. Consequently, absolute bioavailability values of diltiazem pretreated with atorvastatin (8.4-10.6%)were significantly higher (p < 0.05) than that in the control group (6.6%). Although the pretreatment of atorvastatin significantly (p < 0.05) increased the AUC of desacetyldiltiazem, metabolite-parent AUC ratio (M.R.) in the presence of atorvastatin (0.5 or 2.0 mg x kg(-1)) was significantly decreased compared to the control group, implying that atorvastatin could be effective to inhibit the metabolism of diltiazem. In conclusion, the concomitant use of atorvastatin significantly enhanced the oral exposure of diltiazem in rats.

Effects of Ticlopidine on the Pharmacokinetics of Diltiazem and Its Main Metabolite, Desacetyldiltiazem, in Rats

“…And this result was also consistent with a previous report in which oral administration of fl uvastatin or atorvastatin, inhibitors of CYP3A4, signifi cantly increased the AUC and C max of diltiazem in rats (Choi et al, 2006;Hong et al, 2007).…”

Effects of pravastatin on the pharmacokinetic parameters of nimodipine after oral and intravenous administration in rats: Possible role of CYP3A4 inhibition by pravastatin

“…These results were consistent with reports that simvastatin significantly increased the AUC and C max of verapamil in rats,[26] and atorvastatin also significantly increased the bioavailability of diltiazem in rats. [27] However, these results are not consistent with reports by Yang et al . showing that pravastatin did not significantly increase the AUC and C max of losartan in rats.…”

Pharmacokinetics and metabolism of diltiazem in rats: comparing single vs repeated subcutaneous injections in vivo

“…CYP3A4 and CYP2D6), drug-drug interactions and the concept of active metabolites [20][21][22][23]. The reasons for higher plasma concentrations of DTZ resulted from repeated doses are still questions that need to be addressed.…”

“…Although DTZ has been in clinical use for over 20 years, it is still one of the most frequently used drugs to study the principles of pharmacokinetic and metabolism particularly those related to CYP450 s (e.g. CYP3A4 and CYP2D6), drug-drug interactions and the concept of active metabolites [20][21][22][23]. The reasons for higher plasma concentrations of DTZ resulted from repeated doses are still questions that need to be addressed.…”