Weir S J, Ueda C T
Department of Pharmaceutical Sciences, University of Nebraska Medical Center, College of Pharmacy, Omaha.
J Pharmacol Exp Ther. 1988 Sep;246(3):1026-32.
Hypothyroid, hyperthyroid and euthyroid rats were given 45 or 80 mg/kg i.v. or 100 mg/kg p.o. of amiodarone hydrochloride to determine the effects of thyroid dysfunction on the absorption and disposition characteristics of amiodarone. Serial blood samples were obtained for 48 hr and assayed for amiodarone and desethylamiodarone by high-performance liquid chromatography. In the hypothyroid rats, reductions in amiodarone clearance (CL) of 73% (26.9-7.3 ml/min/kg) and 61% (18.7-7.3 ml/min/kg) were observed with the 45- and 80-mg/kg i.v. bolus doses, respectively. Accompanying the decreases in CL were increases in the terminal disposition half-life (T1/2 gamma), 89% (18-34 hr) with the 45-mg/kg dose and 185% (20-57 hr) after the 80-mg/kg dose. The steady state (Vss) and apparent (Vd) volumes of distribution were smaller at the lower dose but were invariant after administration of the larger dose. Furthermore, the central compartment volume was not altered. In the hyperthyroid rats, a 67% increase in CL (12.8-21.4 ml/min/kg) and 75 to 80% increases in Vss (15.5-27.1 liters/kg) and Vd (25.0-44.8 liters/kg) were observed with the 45-mg/kg of amiodarone dose. However, no changes in CL, Vd and Vss were seen with the 80-mg/kg dose. Furthermore, gamma, T1/2 gamma and central compartment volume were not altered in the hyperthyroid rats. The effects of thyroid dysfunction on the p.o. bioavailability characteristics of amiodarone were minor. These studies demonstrated that the disposition kinetics of amiodarone are altered in hypo- and hyperthyroidism.
给甲状腺功能减退、甲状腺功能亢进和甲状腺功能正常的大鼠静脉注射45或80mg/kg或口服100mg/kg盐酸胺碘酮，以确定甲状腺功能障碍对胺碘酮吸收和处置特性的影响。连续48小时采集血样，并用高效液相色谱法测定胺碘酮和去乙基胺碘酮。在甲状腺功能减退的大鼠中，静脉推注45mg/kg和80mg/kg剂量的胺碘酮后，胺碘酮清除率（CL）分别降低了73%（26.9 - 7.3ml/min/kg）和61%（18.7 - 7.3ml/min/kg）。伴随CL降低的是终末处置半衰期（T1/2γ）增加，45mg/kg剂量时增加89%（18 - 34小时），80mg/kg剂量后增加185%（20 - 57小时）。较低剂量时稳态分布容积（Vss）和表观分布容积（Vd）较小，但给予较大剂量后不变。此外，中央室容积未改变。在甲状腺功能亢进的大鼠中，给予45mg/kg胺碘酮剂量后，CL增加67%（12.8 - 21.4ml/min/kg），Vss增加75%至80%（15.5 - 27.1升/kg），Vd增加75%至80%（25.0 - 44.8升/kg）。然而，80mg/kg剂量时CL、Vd和Vss未见变化。此外，甲状腺功能亢进的大鼠中γ、T1/2γ和中央室容积未改变。甲状腺功能障碍对胺碘酮口服生物利用度特性的影响较小。这些研究表明，甲状腺功能减退和亢进时胺碘酮的处置动力学发生改变。
