토끼에서 나린진이 딜티아젬과 그대사체, 디아세틸딜티아젬의 생체이용율에 미치는 영향

Effect of Pretreatment of Naringin on the Bioavailability of Diltiazem and Deacetyldiltiazem in Rabbits

The purpose of this study was to investigate the effect of naringin pretreatment on the bioavailability and pharmacokinetics of diltiazem and one of its metabolites, deacetyldiltiazem, in rabbits. Pharmacokinetic parameters of diltiazem and deacetyldiltiazem were determined after oral administration of diltiazem (15 mg/kg) pretreated with naringin (1.5, 7.5 and 15 mg/kg). Absorption rate constant (ka) of diltiazem after oral administration of diltiazem pretreated with naringin was significantly (p<0.05 or p<0.01) increased compared to the control group. Area under the plasma concentration-time curve (AUC) and peak concentration (Cmax) of the diltiazem were significantly (p<0.05 or p<0.01) higher than those of the control. Absolute bioavailability (AB%) of diltiazem pretreated with naringin ranged from 13.5% to 18.6%, being enhanced compared to that of the control, 7.2%. Relative bioavailability (RB%) of diltiazem was 1.9~2.6 times higher than that of the control group. There was no significant change in terminal half-life (t1/2) and Tmax of diltiazem in the presence of naringin. AUC of deacetyldiltiazem pretreated with naringin was significantly (p<0.05) higher than (p<0.05) that of the control. But the metabolite ratios (MR) were significantly decreased (p<0.05), implying that pretreatment of naringin could be effective to inhibit the CYP 3A4-mediated metabolism of diltiazem. In this study, pretreatment of naringin significantly enhanced the oral bioavailability of diltiazem. These results suggested that the diltiazem dosage should be adjusted when it is administered with naringin or a naringin-containing dietary supplement in the clinical setting.