Abstract

A deterministic approach to the bimolecular and irreversible interaction of chemicals with receptors was used to develop pharmacodynamic relationships which are applicable in teratology. Pharmacokinetic principles governing the rates of absorption, distribution, metabolism and elimination of drugs were incorporated into a general model to yield equations which quantitate the effects of two classes of chemical teratogens. Compounds such as thalidomide and cyclophosphamide, called class I teratogens, have no minimum embryopathic dose, and there is a linear relation with a negative slope between the dose of teratogen and the logarithm of the fraction of unaffected embryos or fetuses. The slope of the graph and the TD5O (dose which produces 50% embryopathy) were related to the teratogen-receptor association rate constant and the integral of drug amount in the receptor compartment over time. Drugs such as hydroxyurea and 5-fluorouracil, called class II teratogens, have dose-effect curves which are related to the same factors at large doses. However, these compounds also have a minimum dose intercept which can be related to a threshold number of drug-receptor interactions which elicits the initial effect. These relationships, in general, characterize drugs which attach irreversibly to cell receptors in the process of producing their pharmacologic or toxic effects.