The Effect of Naringin on Pharmacokinetics of Tamoxifen in Rats

Abstract

본 연구의 목적은 나린진(1.5, 7.5, 15 mg/kg)으로 병용투여 혹은 0.5시간이 전처리된 흰쥐에게 타목시펜(10 mg/kg)을 경구투여하였을 때 타목시펜의 약물동태에 미치는 영향을 연구하려고 한다. 나린진을 병용투여 혹은 전처리했을 때 타목시펜 혈장중농도는 대조군에 비해 유의성 있게(p<0.01 : 전처리군 ; p< 0.05 at 1.5 mg/kg, p<0.01, at 7.5 and 15 mg/kg : 병용투여군) 증가하였다. 나린진으로 전처리하였을 때 타목시펜의 혈장농도 곡선하면적(AUC)과 최고혈장농도(Cmax)는 대조군에 비해 유의성(p<0.01) 있게 증가되었고, 병용투여하였을 때에도 유의성(p< 0.05 at 1.5 mg/kg; p<0.01, at 7.5 and 15 mg/kg) 있게 증가되었다. 나린진으로 전처리하였을 때 타목시펜의 흡수속도정수(Ka) 또한 대조군에 비해 유의성(p<0.01) 있게 증가되었고, 병용투여하였을 때에도 유의성(p< 0.05 at 1.5 mg/kg; p<0.01, at 7.5 and 15 mg/kg) 있게 증가되었다. 나린진을 병용투여하였을 때 타목시펜의 절대생체이용률 AB%은 대조군(31.2%) 보다 높다(59.8-85.9%). 나린진으로 전처리시 타목시펜의 AB%은 병용투여군 보다 더 높았다(63.8-93.6%). 나린진으로 전처리된 흰쥐와 나린진이 병용투여된 흰쥐 모두의 타목시펜 생체이용률은 대조군에 비해 유의성 있게 증가되었다. 최고농도도달시간(Tmax), 소실속도정수(Kel) 반감기(t½)에 있어서는 유의성을 나타내지 못하였다. 두 군에서 타목시펜의 생체이용률이 증가하는 것은 나린진이 초회통과의 대사과정에서 CYP 3A4 효소나 P-glycoprotein efflux pump를 저해하는 것에 기인하는 것으로 사료된다.|The aim of this study was to investigate the effect of naringin on the pharmacokinetics of tamoxifen after administration of tamoxifen (10 mg/kg) orally to rats either co-administered or pretreated with naringin (1.5, 7.5, 15 mg/kg). Pretreatment (p<0.01) and co-administration of naringin increased the plasma concentrations of tamoxifen in (p< 0.05 at 1.5 mg/kg; p<0.01, at 7.5 and 15 mg/kg) significantly when compared with the control. The areas under the plasma concentration-time curve (AUC) and the peak concentration (Cmax) of tamoxifen in both pretreatment (p<0.01) and co-administration (p< 0.05 at 1.5 mg/kg; p<0.01, at 7.5 and 15 mg/kg) group were significantly higher than the control. The absolute bioavailability (AB%) of tamoxifen in the rats pretreated with naringin was higher (63.8-93.6%) than the control (31.2%), and that in the rats co-administered with naringin was also higher (59.8-85.9%) than the control(31.2%). The absorption rate constant (Ka) of tamoxifen pretreated or coadministed with naringin was prolonged significantly (p<0.01) compared to the control. There were no apparent changes in the time to reach peak concentration (Tmax), elimination rate constant (Kel) and terminal half-life (t½) of tamoxifen with co-administration or pretreatment. The oral bioavailibility of tamoxifen in both co-administration and pretreatment group was increased significantly compared with the control. The increased oral bioavailability of tamoxifen with naringin might result from the fact that naringi inhibits the efflux pump P-glycoprotein and the first-pass metabolizing enzyme CYP 3A4.