INTERSPECIES VARIABILITY IN MITOXANTRONE METABOLISM USING PRIMARY CULTURES OF HEPATOCYTES ISOLATED FROM RAT, RABBIT AND HUMANS

Metabolism of mitoxantrone was studied in primary cultures of hepatocytes freshly obtained from rat, rabbit and humans. Metabolic pattern was evaluated by a high performance liquid chromatographic method which specifically resolved mitoxantrone from its mono- and dicarboxylic acid derivatives. Studies were carried out over 48 hr and at [C-14]mitoxantrone concentrations ranging between 1 and 20-mu-M. In all species studied, metabolism occurred: extracellular unchanged mitoxantrone concentrations represented around 50, 25 and 20% of total extracellular radiolabel at 48 hr in rat, rabbit and humans, respectively. Although minor interspecies variability was observed in total amount of drug biotransformed by hepatocytes, large variability in the metabolic pattern occurred between the different species: hence, in rats the main derivatives were two polar compounds and only trace amounts of the mono- and dicarboxylic acid metabolites were present. In both rabbits and humans however, these polar derivatives represented minor metabolic pathways and the main metabolites were the mono- and dicarboxylic acid derivatives. While the percentage of total biotransformation was similar in these two latter species, the monocarboxylic acid derivative was the main metabolite in rabbits while the dicarboxylic acid was predominant in humans. Only small interindividual differences (N = 4) were observed in the metabolism of mitoxantrone by human hepatocytes in primary culture. These data demonstrated that: (i) in all species, mitoxantrone was biotransformed into metabolites which rapidly effluxed in the extracellular compartment, (ii) there were low interspecies differences between rat, rabbit and humans in terms of total biotransformed drug, but (iii) large interspecies variability was demonstrated in the qualitative (rat versus both rabbit and human) and relative (rabbit versus man) patterns of the metabolites. Furthermore, the metabolism of mitoxantrone was linear over a wide range of concentrations (i.e. 1-20-mu-M). In conclusion, rabbit appears to be the animal species most closely related to humans in terms of mitoxantrone metabolism.