Age-related changes in ouabain pharmacology. Ouabain exhibits a different volume of distribution in adult and young dogs

Abstract

To better understand why one must administer much higher doeses of digitalis glycosides to immature than to mature humans and animals, we studied ouabain pharmacokinetics in adult and young dogs. Consistent with reported observations that ouabain-binding, metabolism, and excretion do not change with age, we found no significant differences in the transfer coefficients in a linear two-compartment open model for ouabain pharmacokinetics following a bolus of 0.05 mg/kg. We did find, however, that young dogs had nearly twice the ouabain volumes of distribution per kilogram of body weight as adults (155.4 +/- 1.2 (SE) ml/kg vs. 80 +/- 0.6, P less than 0.0005) and that one could account for this difference with the fact that young dogs had nearly twice the plasma volume 108 +/- 9.8, vs. 68 +/- 7.3, P = 0.001) and interstitial fluid space (318 +/- 35 vs. 190 +/- 6.5, P = 0.006) as the adults. For the same dose per kilogram, left and right ventricular ouabain concentrations were inversely related to the volume of distribution, with the adults having significantly higher tissue levels and incidence of arrhythmias. One must give more ouabain to a young dog to get the same plasma concentration as in an adult because the mass of ouabain in rapid equilibrium with the plasma is diluted in a larger volume of distribution.