Species Differences in Drug Metabolism

Abstract

The importance of species differences in drug metabolism in understand­ ing the mechanism of action of many drugs has become increasingly evi­ dent. Several reviews and articles on the overall topic of drug metabolism have covered aspects of it (1-17). In addition, discussion of species differ­ ences in drug metabolism formed an important segment of a recent sympo­ sium, the proceedings of which contain a number of very informative papers (18-24). It would appear that the increasing interest in the subject stems from the premise that improved understanding and broader knowledge of species differences in drug metabolism will greatly improve our abilities to predict the pharmacologic and toxic010gic properties of a given compound in man from experimental data obtained in animals. It should also be pointed out that such studies, even when only indirectly reIated to drug therapy, have yielded valuable new biochemical information of quite fundamental nature. Examples of this type concern acetyl CoA, the role of pyridine nucleotides in oxygen incorporation, mechanisms of enzyme adaptation, human genetics, phylogenetic and ontogenetic enzyme development, intracellular structure, organ and membrane function, and biosynthesis of vitamin C (25). The in­ creased interest is also probably correlated with recent technological adv­ ances that will possibly enable one to study the physiological disposition and metabolic fate of a compound in several species within a relatively short pe­ riod of time. If the above comments sound encouraging, they may also be unduly opti­ mistic, at least insofar as prediction is concerned. For example, Williams (19) stated that aromatic hydroxylation varies quantitatively and qualita­ tively in haphazard fashion among species, and that one can not, at present, draw definite conclusions about the relationship between drugs, species, and metabolic routes. Brodie (23) is equally discouraging in another sense, namely, the possibility of discovering an animal species, that, drug-metabo­ lism-wise, is greatly similar to man. It should be pointed out here, however, that very little work of this type has been done with the higher nonhuman primates, i.e., the chimpanzee, gorilla, and orang-utan. The reader should also beware of the catchall name monkeysince in many papers it refers to