흰쥐에서 캠페롤과 리코찰콘 A가 니페디핀의 생체이용효율에 미치는 영향

Abstract

The aim of this study was to investigate the possible effects of kaempferol and/or licochalcone A on the bioavailability and pharmacokinetics of nifedipine and its main metabolite, dehydronifedipine, in rats. The bioavailability and pharmacokinetic parameters of nifedipine and dehydronifedipine were determined after oral and intravenous administration of nifedipine to rats in the presence and absence of kaempferol and/or licochalcone A (0.4, 2 and 10 mg/kg). The effect of kaempferol and/or licochalcone A on P-glycoprotein (P-gp) and cytochrome P450 (CYP) 3A4 activity were evaluated. Kaempferol and licochalcone A inhibited CYP3A4 enzyme activity in a concentration-dependent manner with a 50% inhibition concentration (IC50) of 9.8 μM and 3.9 μM. In addition, kaempferol and licochalcone A significantly enhanced the cellular accumulation of rhodamine-123 in MCF-7/ADR cells overexpressing P-gp. The areas under the plasma concentration-time curve (AUC0-∞) of nifedipine was significantly (2 mg/kg, P < 0.05; 10 mg/kg, P < 0.01) increased by 29.3-45.4% and 35.3-55.7%, respectively, with kaempferol and/or licochalcone A . The peak concentration (Cmax) of nifedipine were significantly (2 mg/kg, P < 0.05; 10 mg/kg, P < 0.01) increased by 41.8% and 19.6-52.4%, respectively, with kaempferol and/or licochalcone A. The total body clearance (CL/F) was significantly (2 mg/kg, P < 0.05; 10 mg/kg, P < 0.01) decreased by 22.8-31.3% and 26.0-35.6%, respectively, with kaempferol and/or licochalcone A. Consequently, the absolute bioavailability (AB) of nifedipine in the presence of kaempferol and/or licochalcone A was significantly (2 mg/kg, P < 0.05; 10 mg/kg, P < 0.01) higher by 28.5-44.9% and 34.8-55.7% than that of the control group. Moreover, the relative bioavailability (RB) of nifedipine was 1.29-1.45-fold and 1.35-1.56-fold greater, respectively, with kaempferol and/or licochalcone A than that in the control group. The metabolite-parent AUC ratio (MR) in the presence of kaempferol and/or licochalcone A (10 mg/kg) significantly (P < 0.05) decreased compared to the control group. This result implied that kaempferol and licochalcone A effectively inhibited the metabolism of nifedipine. The increased bioavailability of nifedipine in the presence of kaempferol and/or licochalcone A might be due to an inhibition of the P-gp-mediated efflux transporter in the small intestine and CYP3A-mediated metabolism in the small intestine and/or in the liver and/or to a reduction of total body clearance rather than to a reduction of renal elimination of nifedipine by kaempferol and/or licochalcone A. Therefore, the dose of nifedipine should be adjusted when coadministered with kaempferol and/or licochalcone A for rational dosage regimen.