The Pharmacokinetics of Verapamil and Its Major Metabolite, Norverapamil, After Oral Administration of Verapamil in Rabbits with Hepatic Disorder Induced by Carbon Tetrachloride

Abstract

간장장애가토에서 베라파밀의 약물동태변화에 대한 연구를 시도하였으며, 결과는 다음과 같다. 1) 베라파밀(10 mg/kg)을 경구투여한 후 slight, moderate, severe 간장장애군에서의 베라파밀의 평균혈장중농도는 정상군에 비해 유의성 (p<0.01) 있게 높았다. 2) 베라파밀의 혈장중농도곡선하면적(AUC)은 정상군(319±68 ng/ml·h)에 해서, slight (478 ± 94 ng/ml·h), moderate (622± 129 ng/ml·h) 및 severe (778±151 ng/ml·h) 간장장애군에서 유의성 (p<0.01) 있게 증가하였다. 3) 베라파밀의 최고열중농도(C_(max))는 정상군(30±9.5 ng/ml)에 비해 slight (60±9.1 ng/ml), moderate (90±16.1 ng/ml) 및 severe (120±26.1 ng/ml) 간장장애군에서 유의성 (p<0.01) 있게 높았다. 4) 베라파밀의 절대적 생체이용률(F_(A.B) )은 정상군에서 9.1％이였고 slight (13.6％), moderate (17.7％) 및 severe (22.2％) 간장장애군에서 유의성 (p<0.01) 있게 높았다. 베라파밀의 상대적생체이용률(F_(R.B))도 정상군에 비해 간장장애군에서 유의성(p<0.01) 있게 증가하였다. 이는 베라파밀이 간에서 주로 대사되는데 사염화탄소에 의한 간장장애시 간대사가 감소되었기 때문인것으로 사료된다. 5) 베라파밀의 최고혈중농도 도달시간(T_(max))과 소실반감기(t½)도 간장장애가토에서 유의성(p<0.01, T_(max); p<0.05, t½) 있게 연장되였다. 6) 간장장애가토에서 혈장중 노아베라파밀의 AUC와 C_(max)는 정상군에 비해 severe 간장장애가토에서만 유의성(p<0.05) 있게 감소되었고, 대사체인 노아베라파밀과 베라파밀의 AUC비율(M.R.)은 모두 유의성(p<0.05, slight; p<0.01, moderate and severe) 있게 감소되었다.|The aim of this study was to investigate the pharmacokinetic changes of verapamil and its major metabolite, norverapamil, after oral administration of verapamil (10 mg/kg) in rabbits with slight, moderate and severe hepatic failure induced by carbon tetrachloride. The plasma verapamil concentrations in all groups of hepatic failure were significantly higher (p<0.01) than the control. However, the plasma norverapamil concentrations in severe hepatic failure were significantly lower (p<0.05) than the control. The peak concentrations (C_(max)) and the areas under the plasma concentration-time curve (AUC) of verapamil in the rabbits were significantly (p<0.01) higher than the control. The absolute bioavailability (F_(A.B)) and the relative bioavailability (F_(R.B)) of verapamil in the rabbits with hepatic failure were significantly higher (13.6-22.2％ and 150-244％, respectively) than the control (9.1％ and 100％, respectively). Although the AUC and C_(max) of its major metabolite, norverapamil, in slight, moderate hepatic failure were not significantly lower than the control. The metabolite-parent AUC ratios in all groups of hepatic failure were decreased significantly (p<0.05, in slight group; p<0.01, in moderate and severe group) compared to the control. This could be due to decrease in metabolism of verapamil in the liver because of suppressed hepatic function in the hepatic failure groups because verapamil is mainly metabolized in the liver. These results suggest that doses fo verapamil should be adjusted by degree fo hepatic failure when verapamil is administered to patients with liver disease