Metabolism of the new ribonucleotide reductase inhibitor amidox in the isolated perfused rat liver.
BACKGROUND
Amidox (AX) is a novel anticancer drug currently undergoing pre-clinical studies. Though AX shows activity against various tumor cells, its biotransformation is still unknown.


METHODS
Livers of male Wistar and mutant TR- rats were perfused with AX in a single pass system and bile and effluent perfusate analyzed by HPLC for AX and its metabolites.


RESULTS
In bile, seven biotransformation products but not AX could be quantified though their total excretion into bile was low. However, the cumulative efflux of AX metabolites into the effluent perfusate was high with about 55% of AX applied to the liver during perfusion. Biliary excretion of AX metabolites in TR- rats was substantially reduced compared to Wistar rats, indicating that metabolites are substrates of the canalicular multispecific organic anion transporter cmoat.


CONCLUSIONS
Metabolism of AX in rat liver is high and has to be considered during cancer therapy of patients.
Salamon
A
A
Institute of Pharmaceutical Chemistry, University of Vienna, Althanstrasse 14, A-1090 Vienna, Austria.
Vielnascher
E
E
Hagenauer
B
B
Szekeres
T
T
Szekeres-Fritzer
M
M
Thalhammer
T
T
Jäger
W
W
D000818:Animals; D027321:Anion Transport Proteins; D000970:Antineoplastic Agents / Q000378:metabolism / Q000493:pharmacokinetics*; D001646:Bile / Q000378:metabolism; D001711:Biotransformation; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D019008:Drug Resistance, Neoplasm; D004791:Enzyme Inhibitors / Q000378:metabolism / Q000493:pharmacokinetics; D008099:Liver / Q000378:metabolism*; D008297:Male; D010091:Oximes / Q000378:metabolism / Q000493:pharmacokinetics*; D010477:Perfusion; D051381:Rats; D011922:Rats, Mutant Strains; D017208:Rats, Wistar; D012264:Ribonucleotide Reductases / Q000037:antagonists & inhibitors
D027321:Anion Transport Proteins; D000970:Antineoplastic Agents; D002352:Carrier Proteins; D004791:Enzyme Inhibitors; D010091:Oximes; C070491:Amidox; D012264:Ribonucleotide Reductases