Comparative aspects of drug conjugation in laboratory animals, exotic species and man

Abstract

The great majority of xenobiotics entering the animal body undergo enzymic metabolism in a biphasic sequence of reactions, involving first a reaction of oxidation, reduction or hydrolysis, followed by conjugation of the product with an endogenous moiety. Six major conjugation reactions may be discerned, involving glucuronic acid, sulfate, methyl or acetyl groups, glutathione or one of a number of amino acids. In addition, a number of novel conjugations are known. Although the fundamental pattern of metabolism is common to all species, there occur within the pattern substantial phylogenetic differences, both qualitative and quantitative. These are especially evident with the major conjugation reactions, certain of which exhibit “species defects”, for example glucuronidation in the cat and N-acetylation in the dog, while other reactions are restricted in their occurrence to particular groups of species: this is noteworthy with respect to primate species. An understanding of the characteristics of xenobiotic metabolism in particular species may have taxonomic value. It is increasingly appreciated that the conjugation reactions are of considerable pharmacological and toxicological significance, generally by favouring detoxication and excretion. There do exist, however, circumstances where conjugation results in metabolic activation. In either situation, the occurrence of substantial species differences in conjugative metabolism frequently underlies interspecies differences biological activity of xenobiotics.