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

Background: this study aimed to investigate the effects of hmg-coa reductase inhibitors on the pharmacokinetics of nifedipine in rats.methods: we determined the pharmacokinetic parameters of nifedipine and dehydronifedipine in rats after oral and intravenous administration of nifedipine without and with hmg-coa reductase inhibitors. we evaluated the effect of hmg-coa reductase inhibitors on the activity of p-glycoprotein (p-gp) and cytochrome p450 (cyp) 3a4.results: atorvastatin,fluvastatin,pravastatin and simvastatin inhibited cyp3a4 activities; inhibitory concentration (ic50) values were 47.0,5.2,15.0 and 3.3 μm,respectively. simvastatin and fluvastatin increased the cellular uptake of rhodamine-123. the area under the plasma concentration-time curve (auc0-∞) and the peak plasma concentration (cmax) of oral nifedipine were significantly increased by fluvastatin and simvastatin,respectively,compared to control group. the total body clearance (cl/f) of nifedipine after oral administration with fluvastatin and simvastatin were significantly decreased compared to those of control. the metabolite-parent auc ratio (mr) of nifedipine with fluvastatin and simvastatin were significantly decreased,which suggested that fluvastatin and simvastatin inhibited metabolism of nifedipine,respectively. the auc0-∞ of intravenouse nifedipine with fluvastatin and simvastatin was significantly higher than that of the control group.conclusion: the increased bioavailability of nifedipine may be mainly due to inhibition of both p-gp in the small intestine and cyp3a subfamily-mediated metabolism of nifedipine in the small intestine and/or in the liver and to the reduction of the cl/f of nifedipine by fluvastatin and simvastatin. © 2014 institute of pharmacology,polish academy of sciences. published by elsevier urban & partner sp. z o.o. all rights reserved.