The Role of Toxicokinetics in Developmental Toxicity Testing: Lessons from Comparative Developmental Drug Metabolism

Abstract

Enzymes, receptors, and other proteins have their own distinct developmental profiles. Consequently, developmental toxicity tests should be designed keeping the maturation process in mind. Among developmentally-controlled functions, the enzymes metabolizing xenobiotics are of importance, because the kinetics of most drugs is critically dependent on the activity of these enzymes. Most drug-metabolizing enzymes are rather poorly developed in fetuses of common experimental animals, whereas human fetuses possess quite an active complex of xenobiotic-metabolizing enzymes in their livers. Quite drastic changes in enzyme activities occur around and after birth. Due to large species differences—especially between humans and common experimental animals, and due to continuous, sometimes very rapid changes in the course of development, some safeguards should be built into developmental toxicity tests to aid the extrapolation of the findings across species and age groups. The dose-concentration-effect relationships and the production of metabolites, especially those biologically active, as a function of development, should be studied as an integral part of any developmental toxicity test.