Abstract
Pharmacokinetics has evolved into a highly interactive discipline in which the dispositional characteristics of an administered drug are often compared to the time course of observed drug effects. The more recent discipline of toxicokinetics is undergoing a similar, although belated, evolution. While toxicokinetic studies were first intended to demonstrate merely that toxicology test animals received drug, they now provide a critical evaluation of drug disposition at toxicologic doses and also the relationships between toxicokinetic values and the occurrence and time course of toxic events. Different dose levels used in toxicokinetics, compared to pharmacokinetics, give rise to technological changes in such factors as solubility, stability, absorption, presystemic clearance, protein binding, and metabolism that may be influenced by dose size, and may give rise to profound differences in the design and interpretation of studies. Pharmacokinetic and toxicokinetic studies also have different objectives. While preclinical pharmacokinetic and pharmacodynamic studies provide correlates, based on generally well-established parameters, that may provide useful but perhaps not essential information to guide drug dosage in man, information from toxicokinetics and toxicodynamic studies, which is difficult to obtain because of capricious interspecies differences in dispositional characteristics and organ/tissue sensitivities, is critical to predict the behavior and safety of compounds in man.