title: Effects of nifedipine on the pharmacokinetics of repaglinide in rats: possible role of CYP3A4 and P-glycoprotein inhibition by nifedipine.
abstract: BACKGROUND
  The aim of this study was to investigate the effects of nifedipine on the bioavailability and pharmacokinetics of repaglinide in rats.
  
  
  METHODS
  The effect of nifedipine on P-glycoprotein (P-gp) and cytochrome P450 (CYP) 3A4 activity was evaluated. The pharmacokinetic parameters of repaglinide and blood glucose concentrations were also determined in rats after oral (0.5 mg/kg) and intravenous (0.2 mg/kg) administration of repaglinide to rats in the presence and absence of nifedipine (1 and 3 mg/kg).
  
  
  RESULTS
  Administration of nifedipine resulted in inhibition CYP3A4 activity with an IC50 value of 7.8 μM, and nifedipine significantly inhibited P-gp activity in a concentration-dependent manner. Compared to the oral control group, nifedipine significantly increased the area under the plasma concentration-time curve (AUC0-∞) and the peak plasma concentration (Cmax) of repaglinide by 49.3 and 25.5%, respectively. Nifedipine significantly decreased the total body clearance (CL/F) of repaglinide by 22.0% compared to the oral control group. Nifedipine also increased the absolute bioavailability (AB) of repaglinide by 50.0% compared to the oral control group (33.6%). In addition, the relative bioavailability (RB) of repaglinide was 1.16- to 1.49-fold greater than that of the control group. Compared to the intravenous control, nifedipine significantly increased AUC0-∞ of repaglinide. Blood glucose concentrations had significant differences compared to the oral control groups.
  
  
  CONCLUSIONS
  Nifedipine enhanced the oral bioavailability of repaglinide, which may be mainly attributable to inhibition of CYP3A4-mediated metabolism of repaglinide in the small intestine and/or in the liver and to inhibition of the P-gp efflux transporter in the small intestine and/or reduction of total body clearance by nifedipine. The current study has raised awareness of potential drug interactions by concomitant use of repaglinide with nifedipine.
authors.affiliation: Department of Food and Drug, Chosun University, Gwangju 501-759, Republic of Korea. dhchoi@chosun.ac.
authors.forename: Jin-Seok
authors.initials: JS
authors.lastname: Choi
authors.forename: In
authors.initials: I
authors.lastname: Choi
authors.forename: Dong-Hyun
authors.initials: DH
authors.lastname: Choi
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000284:Administration, Oral; D000818:Animals; D019540:Area Under Curve; D001682:Biological Availability; D015415:Biomarkers / Q000097:blood; D001711:Biotransformation; D001786:Blood Glucose / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000008:administration & dosage*; D002219:Carbamates / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D065692:Cytochrome P-450 CYP3A Inhibitors; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000008:administration & dosage*; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D007275:Injections, Intravenous; D008297:Male; D009543:Nifedipine / Q000008:administration & dosage*; D010880:Piperidines / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D019338:Polypharmacy; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D015415:Biomarkers; D001786:Blood Glucose; D002121:Calcium Channel Blockers; D002219:Carbamates; D065692:Cytochrome P-450 CYP3A Inhibitors; D004791:Enzyme Inhibitors; D007004:Hypoglycemic Agents; D010880:Piperidines; C072379:repaglinide; C465260:Cyp3a2 protein, rat; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D009543:Nifedipine