Absorption and distribution of xenobiotics

Extrapolation of pharmacokinetic data between species has been simplified by the advent of more sensitive methods of analysis of chemicals in body tissues and by the capability of inexpensive computers to perform complex calculations. These new methods enable investigators to observe the rates at which target tissues reach equilibrium in different species and to develop mathematical models of these processes. The evaluation of physiological pharmacokinetics from classical or compartmental kinetics is improving the ability to project the long-term behavior of chemicals in body fluids and organs based on independently derived physical, chemical, and physiological constants obtained from simple chemical reactions, tissue culture experiments, or short-term animal studies. Accurate prediction of chemical behavior by such models gives support to hypothetical mechanisms of distribution and accumulation, while significant deviations from predicted behavior signal the existence of previously unsuspected pathways. These techniques permit the simulation of the impact of linear, nonlinear, and saturation kinetics on chemical behavior; the prediction of integrated tissue exposure; and the mapping of the sequence of alternate metabolic pathways that lead to toxicity or detoxification. The discussion will identify the research needs for improving extrapolations between species.