Evans R L, Owens S M, Ruch S, Kennedy R H, Seifen E
Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock 72205.
Toxicol Appl Pharmacol. 1990 Jan;102(1):61-7. doi: 10.1016/0041-008x(90)90083-7.
Digoxin protein binding and pharmacokinetics were studied in 4-, 14-, and 25-month-old male Fischer-344 rats to determine if there were age-dependent changes in digoxin disposition. Serum protein binding did not differ among age groups. The average percentage unbound digoxin for all animals was 61.3 +/- 5.3% (means +/- SD, n = 15). For pharmacokinetic studies, [3H]digoxin and 1 mg/kg unlabeled digoxin were administered as an intravenous bolus dose to animals from each age group. The [3H]digoxin terminal elimination half-life was 2.0, 2.3, and 2.5 hr, respectively. The steady-state volume of distribution in the three age groups was 1.51, 1.49, and 1.27 liters/kg, respectively. Total body clearance for the three age groups was 14.2, 12.1, and 7.5 ml/min/kg, respectively. Analysis of variance of these data followed by Duncan's multiple range test indicated a significant decrease in clearance in the aged rats (25-month-old, p less than 0.05). This age-dependent decrease in clearance suggested that digoxin pharmacokinetics could be a significant factor in age-related alterations in digoxin cardiotoxicity in the rat, as it is in humans, and that the Fischer-344 rat could be a useful model for studies of digoxin pharmacokinetic changes with age.
在4月龄、14月龄和25月龄的雄性Fischer-344大鼠中研究了地高辛的蛋白结合及药代动力学，以确定地高辛处置是否存在年龄依赖性变化。各年龄组间血清蛋白结合无差异。所有动物未结合地高辛的平均百分比为61.3±5.3%（均值±标准差，n = 15）。对于药代动力学研究，将[3H]地高辛和1mg/kg未标记地高辛作为静脉推注剂量给予各年龄组的动物。[3H]地高辛的终末消除半衰期分别为2.0、2.3和2.5小时。三个年龄组的稳态分布容积分别为1.51、1.49和1.27升/千克。三个年龄组的总体清除率分别为14.2、12.1和7.5毫升/分钟/千克。对这些数据进行方差分析，随后进行邓肯多重极差检验，结果表明老年大鼠（25月龄）的清除率显著降低（p < 0.05）。这种清除率的年龄依赖性降低表明，与人类一样，地高辛药代动力学可能是大鼠地高辛心脏毒性年龄相关改变的一个重要因素，并且Fischer-344大鼠可能是研究地高辛药代动力学随年龄变化的有用模型。
