Pharmacokinetics and drug metabolism in the design and interpretation of developmental toxicity studies

A direct teratogenic effect will depend on the concentration-time relationship of the drug or its active metabolite in the placental-embryonic compartment during the sensitive stages of gestation. Pharmacokinetic studies are therefore important for the interpretation and design of teratogenicity experiments, particularly for the problem of species differences, and for attempts to extrapolate experimental findings to the human (“risk assessment”). Pharmacokinetic studies are also crucial in elucidating whether the parent drug or a metabolite is the proximate or ultimate toxic entity. Finally, it is shown that structure-activity studies can greatly benefit from pharmacokinetic experiments to demonstrate whether the teratogenicity of a substance is related to its intrinsic activity or to the extent of placental transfer or both.