title: 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.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Medical Management, Chodang University, Mooan, Republic of Korea.
authors.forename: Chong-Ki
authors.initials: CK
authors.lastname: Lee
authors.affiliation: College of Pharmacy, Chosun University, Pilmundero, Donggu, Gwangju, Republic of Korea.
authors.forename: Jun-Shik
authors.initials: JS
authors.lastname: Choi
authors.affiliation: College of Medicine, Chosun University, Pilmundero, Donggu, Gwangju, Republic of Korea. Electronic address: dhchoi@chosun.ac.kr.
authors.forename: Dong-Hyun
authors.initials: DH
authors.lastname: Choi
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors*; D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology; D019540:Area Under Curve; D001711:Biotransformation; D002121:Calcium Channel Blockers / Q000493:pharmacokinetics*; D051544:Cytochrome P-450 CYP3A / Q000187:drug effects*; D065692:Cytochrome P-450 CYP3A Inhibitors / Q000494:pharmacology*; D004347:Drug Interactions; D005456:Fluorescent Dyes; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007654:Ketoconazole / Q000494:pharmacology; D008297:Male; D009543:Nifedipine / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020112:Rhodamine 123
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000935:Antifungal Agents; D002121:Calcium Channel Blockers; D065692:Cytochrome P-450 CYP3A Inhibitors; D005456:Fluorescent Dyes; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D020112:Rhodamine 123; C465260:Cyp3a2 protein, rat; D051544:Cytochrome P-450 CYP3A; D009543:Nifedipine; D007654:Ketoconazole
keywords: CYP3A4; HMG-CoA reductase inhibitors; Nifedipine; P-gp; Pharmacokinetics