Age-Related Changes In Ouabain Pharmacokinetics

Abstract

Young animals and humans frequently require higher doses of digitalis glycoside per kilogram of body weight or per square meter of body surface area than adult to induce the digitalis effect or toxicity. In order to investigate the pharmacokinetic basis for this observation, we studied pharmacokinetic properties of the relatively polar and rapidly acting cardiac glycoside, ouabain, in adult and young rabbits. Consistent with reported observations, we found no significant difference in transfer coefficients in a linear two compartmental open model for ouabain pharmacokinetics following a 0.05 mg/kg bolus. However, we found that young rabbits had larger ouabain volume of distribution per kilogram of body weight than adults (Vc; 274.36±24.24(S.E.) mllkg vs. 138.29±7.51, Vdss; 1580.61±75.77 mllkg vs. 1056.01±88.18, p<0.005), and a larger systemic clearance (9.18±0.74 mllkg/min vs. 4.67 ±0.80, P<O.Ol). One could account for this difference by the fact that adult rabbits had nearly twice the serum concentrations at the same dose per kilogram, throughout the experimental period. Left and right ventricular ouabain concentrations were inversely related to the volumes of distribution, with significantly higher tissue levels in adult animals. Although the reason for the difference of tissue sensitivity to a given digitalis glycoside concentration remains unclear, the result of this study suggests that the pharmacokinetic difference is responsible for age-related tolerance to digitalis glycoside doses.