The Relationship of Age to the Pharmacokinetics of Early Drug Distribution

The optimal dose of thiopental depends both on its initial distribution kinetics, which determine its concentrations at sites of action after iv administration, and on its pharmacodynamics. The disposition of concomitantly administered thiopental and indocyanine green (ICG), a marker of intravascular space, was determined in 21 patients, aged 20-80 yr, to determine the pharmacokinetic basis of increased reactivity of the elderly to thiopental. Data obtained from frequent early arterial blood samples and the simultaneous modelling of thiopental disposition with that of ICG allow a rigorous description of early drug distribution. Their disposition is described by a two-compartment ICG model and a four-compartment thiopental model that have a common central volume, V1, the central blood pool. ICG distributes, by intravascular mixing, from V1 to a peripheral blood volume that is a subset of a rapidly equilibrating (fast) peripheral thiopental compartment; elimination clearance of both drugs is modelled from these peripheral compartments. In contrast to the results of others, the results of this study demonstrate that V1 does not decrease with increasing age. The only pharmacokinetic variable that changed with age is the intercompartmental clearance (Cl21) from V1 to the rapidly equilibrating peripheral volume, V2, which decreased 35% between the ages of 20-80 yr. The authors suggest that V1 and the intercompartmental clearances may be used together to explain smaller dose requirements in individuals with increased reactivity to thiopental; such an analysis does not predict that dose adjustments should be made on the basis of age alone.