흰쥐에서 아피제닌이 로살탄의 생체이용율에 미치는 영향

Abstract

본 연구에서는 항산화제, 항염증제인 아피제닌이 고혈압치료제인 로살탄의 약물동태에 미치는 영향을 연구검토하였다. 아피제닌(0.5, 2.5 및 10 mg/kg)과 로살탄을 흰쥐에 경구(1 mg/kg) 및 정맥(0.3 mg/kg)으로 병용투여하여 본 연구를 실시하였다. 혈장농도곡선하면적 (AUC) 및 최고혈중농도(Cmax)는 대조군에 비해 아피제닌 병용투여군에서 유의성(P<0.05) 있게 증가하였다. 대조군에 비해 아피제닌 병용투여군에서 절대적생체이용율(AB)은 유의성(P<0.05) 있게 증가되었다. 그 결과로 상대적생체이용율(RB)이 1.26-1.92 배 증가되었다. 이 결과는 아피제닌이 소장 또는 간장에서 CYP3A4와 P-gp를 억제시킴으서 로살탄의 생체이용율이 증가된것으로 사료된다. 아피제닌의 용량증가와 더불어 로살탄의 생체이용율도 증가되었다. 임상에서 아피제닌과 로살탄의 병용투여시 로살탄의 용량을 조절하는 것이 바람직하다고 사료된다.|The present study was to investigate the effect of apigenin, a flavonoid, on the pharmacokinetics of losartan and its active metabolite, EXP-3174, in rats. Pharmacokinetic parameters of losartan and EXP-3174 in rats were determined after an oral administration of losartan (1 mg/kg) in the presence or absence of apigenin (0.5, 2.5 and 10 mg/kg). The pharmacokinetic parameters of losartan were significantly altered by the presence of apigenin compared with the control group (given losartan alone). Presence of apigenin significantly (p < 0.05, 2.5 mg/kg; p < 0.01, 10 mg/kg) increased the area under the plasma concentration？time curve (AUC) of losartan by 19.9？91.6% and peak plasma concentration (Cmax) of losartan by 14.8？78.8%. Consequently, the absolute bioavailability (AB) of losartan in the presence of apigenin was 38.9？63.2%, which was enhanced significantly (p < 0.05) compared with the oral control group (32.9%). The relative bioavailability (R.B.) of losartan increased by 1.26- to 1.92-fold in the presence of apigenin. However, there was no significant change in the peak plasma concentration (Tmax) and terminal half-life (t1/2) of losartan in the presence of apigenin. Presence of apigenin (10 mg/kg) significantly increased the AUC (41.1%) of EXP-3174 compared with the control group. Metabolite-parent AUC ratio in the presence of apigenin (10 mg/kg) significantly (p < 0.05) decreased by 26.3 % compared to the control group, implying that presence of apigenin could be effective to inhibit the cytochrome P450 (CYP)3A4-mediated metabolism and P-glycoprotein (P-gp)- mediated efflux of losartan. In conclusion, the presence of apigenin significantly enhanced the oral exposure of losartan, suggesting that concurrent use of apigenin or apigenin-containing dietary supplement with losartan should require close monitoring for potential drug interactions.