Effects of efonidipine on the pharmacokinetics and pharmacodynamics of repaglinide: possible role of CYP3A4 and P-glycoprotein inhibition by efonidipine.
The purpose of this study was to investigate the effects of efonidipine on the pharmacokinetics and pharmacodynamics of repaglinide in rats. 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 efonidipine (1 and 3 mg/kg). Efonidipine inhibited CYP3A4 activity with an IC(50) value of 0.08 μM, and efonidipine significantly inhibited P-gp activity in a concentration-dependent manner. Compared to the oral control group, efonidipine significantly increased the area under the plasma concentration-time curve (AUC(0-∞)) (P < 0.01 for 3 mg/kg) and the peak plasma concentration (C (max)) (P < 0.05 for 3 mg/kg) of repaglinide by 51.3 and 28.6%, respectively. Efonidipine also significantly (P < 0.01 for 3 mg/kg) increased the absolute bioavailability (AB) of repaglinide by 51.5% compared to the oral control group (33.6%). Moreover, efonidipine significantly increased (P < 0.05 for 3 mg/kg) the AUC(0-∞) of intravenously administered repaglinide. Consistent with these kinetic alterations, the hypoglycemic effect in the concurrent administration group was more pronounced than that in the control group (i.e., repaglinide alone) when the drug was given orally. A pharmacokinetic/dynamic model involving 2-compartment open model with inhibition in absorption/elimination and an indirect response model was apparently sufficient in estimating the concentration-time and effect-time profiles of repaglinide with or without efonidipine. Present study has raised the awareness of potential drug interactions by concomitant use of efonidipine with repaglinide, since efonidipine may alter the absorption and/or elimination of repaglinide by the inhibition of CYP3A4 and P-gp efflux pump. Therefore, the concurrent use of efonidipine with repaglinide may require a close monitoring for potential drug interactions.
College of Pharmacy, Chosun University, Gwangju, 501-759, Republic of Korea.
Cheng
C
Li
Dong-Hyun
DH
Choi
Jun-Shik
JS
Choi
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D019540:Area Under Curve; D055162:Biocatalysis / Q000187:drug effects; D001682:Biological Availability; D001786:Blood Glucose / Q000187:drug effects; D002219:Carbamates / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D065692:Cytochrome P-450 CYP3A Inhibitors; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004095:Dihydropyridines / Q000494:pharmacology*; D004347:Drug Interactions / Q000502:physiology; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D007654:Ketoconazole / Q000494:pharmacology; D008297:Male; D008954:Models, Biological; D009596:Nitrophenols / Q000494:pharmacology*; D009943:Organophosphorus Compounds / Q000494:pharmacology; D000069437:Pharmacological Phenomena / Q000187:drug effects; D010880:Piperidines / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020112:Rhodamine 123 / Q000378:metabolism
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000959:Antihypertensive Agents; D001786:Blood Glucose; D002219:Carbamates; D065692:Cytochrome P-450 CYP3A Inhibitors; D065607:Cytochrome P-450 Enzyme Inhibitors; D004095:Dihydropyridines; D007004:Hypoglycemic Agents; D009596:Nitrophenols; D009943:Organophosphorus Compounds; D010880:Piperidines; D020112:Rhodamine 123; C066425:efonidipine; C072379:repaglinide; D003577:Cytochrome P-450 Enzyme System; C465260:Cyp3a2 protein, rat; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D007654:Ketoconazole