Toxicokinetics of Xenobiotic and Metabolite Distribution and Excretion

Abstract

The first portion of this chapter focusses on physicochemical characteristics of therapeutic and nontherapeutic xenobiotics that have a major influence in determining the rate of onset of pharmacodynamic or toxicodynamic effects in living organisms. This discussion is then extended to the role of these and other factors that affect the extent of distribution and accumulation of xenobiotic and xenobiotic metabolites in the animal or human body. The final portions of the chapter consider the kinetics of excretion of xenobiotics from the body. Simple one-compartment kinetics are reviewed first, followed by multicompartmental systems. In all cases, procedures are proposed that may allow quantification of the systemic ‘dose’ of a xenobiotic exposure to individuals in an environmental or occupational setting, where there is usually little information on the actual exposure. Finally, kinetic models are proposed that may permit determination of the amount of time that it will take for the plasma to be cleared of the xenobiotic, or metabolite, and how this might differ in time for the total body burden to be reduced of the same substances. Keywords: kinetics of toxicodynamic onset; kinetics of distribution and accumulation; kinetics of elimination: one compartment; multicompartmental; dose and exposure determination from kinetic principles; kinetics of plasma clearing in multicompartmental systems; kinetics of clearing of body burden in multicompartmental systems; context-sensitive elimination kinetics