Metabolism of the new ribonucleotide reductase inhibitor amidox in the isolated perfused rat liver

Background: Amidox (AX) is a novel anticancer drug currently undergoing pie -clinical studies. Though AX shows activity, against various tumor cells it s biotransformation is still unknown. Material and Methods: Livers of male Wistar. and mutant TR- rats were perfused with AX in a single pass system a nd bile and effluent perfusate analyzed by HPLC for AX find its metabolites . Results: In bile, seven biotransformation products but not AX could be qu antified though their total excretion into bile was low. However, the cumul ative efflux of AX metabolites into the effluent perfusate was high with ab out 55 % of AX applied to the liver during perfusion. Biliary excretion of AX metabolites in TR- rats was substantially reduced compared to Wistar rat s, indicating that metabolites are substrates of the canalicular multispeci fic organic anion transporter cmoat. Conclusion: Metabblism of RX in I at l iver. is high and has to be considered during cancel therapy of patients.