Comparison of amphetamine metabolism using isolated hepatocytes from five species including human.

Isolated hepatocyte suspensions from rat, rabbit, dog, squirrel monkey and human livers were used to study the metabolism of amphetamine (AMP), a drug for which species-dependent differences in metabolism have been demonstrated in vivo. Hepatocytes were isolated by perfusion of the whole liver or of biopsy specimens. In general, the metabolite profile of hepatocytes from each species corresponded to the profile of urinary metabolites identified previously. Rat hepatocytes primarily metabolized AMP by aromatic hydroxylation to p-hydroxyamphetamine. Rabbit hepatocytes converted AMP almost exclusively to products of the oxidative deamination pathway. Metabolism by hepatocytes from the other three species was mixed, but oxidative deamination was somewhat more active than aromatic hydroxylation in dog, squirrel monkey and human hepatocytes. The overall rate of AMP metabolism differed significantly among the species; the half-life in the hepatocyte suspensions varied about 70-fold, with rabbit less than rat less than dog less than squirrel monkey = human. Metabolism of AMP by human hepatocytes mare closely resembled metabolism by squirrel monkey liver cells than the other species in terms of metabolite profile and rate. However, the disposition of phenylacetone, a product of oxidative deamination of AMP, varied in hepatocytes from the two primate species. Thus, the metabolism of AMP by isolated hepatocytes was unique for each species examined. These studies demonstrate the applicability of isolated hepatocytes to the study of interspecies differences in hepatic xenobiotic metabolism, providing an in vitro technique that can be readily adapted to human liver tissue.