Effects of lovastatin on the pharmacokinetics of verapamil and its active metabolite, norverapamil in rats: Possible role of P-glycoprotein inhibition by lovastatin

Abstract

This study was to investigate the effect of lovastatin on the bioavailability or pharmacokinetics of verapamil and its major metabolite, norverapamil, in rats. The pharmacokinetic parameters of verapamil and norverapamil in rats were measured after the oral administration of verapamil (9 mg/kg) in the presence or absence of lovastatin (0.3 or 1.0 mg/kg). The pharmacokinetic parameters of verapamil were significantly altered by the presence of lovastatin compared to the control group (given verapamil alone). The presence of lovastatin significantly (p < 0.05, 0.3 mg/kg; p < 0.01, 1.0 mg/kg) increased the total area under the plasma concentration-time curve (AUC) of verapamil by 26.5-64.8%, and the peak plasma concentration (C(max)) of verapamil by 34.1-65.9%. Consequently, the relative bioavailability (R.B.) of verapamil was increased by 1.27- to 1.65-fold than that of the control group. However, there was not significant change in the time to reach the peak plasma concentration (T(max)) and the terminal half-life (t(1/2)) of verapamil in the presence of lovastatin. The AUC and C(max) of norverapamil were significantly (p < 0.05) higher than those of presence of 1.0 mg/kg of lovastatin compared with the control group. However, there was no significant change in the metabolite-parent ratio (M.R.) of norverapamil in the presence of lovastatin. The presence of lovastatin significantly enhanced the oral bioavailability of verapamil. The enhanced oral bioavailability of verapamil may be due to inhibition both of the CYP3A-mediated metabolism and the efflux pump P-glycoprotein (P-gp) in the intestine and/or in liver by the presence of lovastatin.

Effects of HMG-CoA reductase inhibitors on the pharmacokinetics of nifedipine in rats: Possible role of P-gp and CYP3A4 inhibition by HMG-CoA reductase inhibitors

“…Subsequently, the relative bioavailability (RB) of nifedipine was increased by 142 and 150% in the presence of fluvastatin and simvastatin (0.8 mg/kg), respectively. Our results were similar to those reported by Choi et al [29] and Hong et al [31] which showed that atorvastatin and lovastatin significantly increased the AUC 0-1 and C max of verapamil, a substrate of both CYP enzymes and P-gp in rats, and by Choi et al [43] which showed that simvastatin significantly increased the AUC and C max of diltiazem in rats. The results of these studies were also consistent with the report that oral diallyl trisulfide (major organosulfur compounds derived from garlic) significantly increased the bioavailability of nifedipine through inhibition of CYP3A4 in rats [46].…”

“…The MR of nifedipine in the presence of fluvastatin and simvastatin (0.8 mg/kg) was significantly (p < 0.05) decreased by 19.0 and 21.0%, respectively compared to that of the control group. These results were similar to those reported by Hong et al [31] and Choi et al [43] which showed that the MR of verapamil and diltiazem in the presence of lovastatin and simvastatin (0.8 mg/kg) was significantly (p < 0.05) decreased, respectively, compared to that of the control group.…”

“…As CYP3A9 expressed in rat corresponds to the ortholog of CYP3A4 in human [27,42,43], and rat CYP3A2 is similar to human CYP3A4 [29,30,44]. Human CYP2C9 and 3A4 and rat CYP2C11 and 3A4 are 77% and 73% homologous, respectively [31,32,45].…”

“…Calcium-channel blockers increase the plasma concentrations of some statins, possibly through the inhibition of CYP 3A4 and P-gp [27,28]. However, few studies have reported about the effects of HMG-CoA reductase inhibitors on the bioavailability or pharmacokinetics of antihypertensive agents [29][30][31][32]. Although a combination of nifedipine and statins have been clinically prescribed for treatment of hypertension, the pharmacokinetic interaction between a HMG-CoA reductase inhibitor and nifedipine in vivo has not been reported thus far.…”

Pharmacological Actions of Statins: A Critical Appraisal in the Management of Cancer

“…The effect of calcium channel antagonists on the pharmacokinetics of statins, by inhibition of CYP3A4 and/or P-gp, has been widely reported (Wang et al, 2001). The coadministration of verapamil, a calcium blocker, substrate of both P-gp and CYP3A4 (Döppenschmitt et al, 1999), with lovastatin or simvastatin (Jacobson, 2004) as well as atorvastatin (Hong et al, 2009) increased their plasma concentrations. These interactions are probably caused by the inhibition of CYP3A-mediated metabolism in small intestine or in the liver and P-gp efflux pump in the small intestine .…”