Metabolism and excretion of the novel bioreductive prodrug PR-104 in mice, rats, dogs, and humans.
PR-104 is the phosphate ester of a 3,5-dinitrobenzamide nitrogen mustard (PR-104A) that is reduced to active hydroxylamine and amine metabolites by reductases in tumors. In this study, we evaluate the excretion of [(3)H]PR-104 in mice and determine its metabolite profile in mice, rats, dogs, and humans after a single intravenous dose. Total radioactivity was rapidly and quantitatively excreted in mice, with cumulative excretion of 46% in urine and 50% in feces. The major urinary metabolites in mice were products from oxidative N-dealkylation and/or glutathione conjugation of the nitrogen mustard moiety, including subsequent mercapturic acid pathway metabolites. A similar metabolite profile was seen in mouse bile, mouse plasma, and rat urine and plasma. Dogs and humans also showed extensive thiol conjugation but little evidence of N-dealkylation. Humans, like rodents, showed appreciable reduced metabolites in plasma, but concentrations of the cytotoxic amine metabolite (PR-104M) were higher in mice than humans. The most conspicuous difference in metabolite profile was the much more extensive O-beta-glucuronidation of PR-104A in dogs and humans than in rodents. The structure of the O-beta-glucuronide (PR-104G) was confirmed by independent synthesis. Its urinary excretion was responsible for 13 +/- 2% of total dose in humans but only 0.8 +/- 0.1% in mice. Based on these metabolite profiles, biotransformation of PR-104 in rodents is markedly different from that in humans, suggesting that rodents may not be appropriate for modeling human biotransformation and toxicology of PR-104.
Gu
Yongchuan
Y
Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.
Atwell
Graham J
GJ
Wilson
William R
WR
D000111:Acetylcysteine / Q000031:analogs & derivatives / Q000378:metabolism; D000328:Adult; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000032:analysis / Q000097:blood / Q000493:pharmacokinetics*; D001646:Bile / Q000737:chemistry; D001711:Biotransformation; D003640:Dealkylation; D004285:Dogs; D005243:Feces / Q000737:chemistry; D020719:Glucuronides / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D005978:Glutathione / Q000031:analogs & derivatives / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D015394:Molecular Structure; D009588:Nitrogen Mustard Compounds / Q000008:administration & dosage / Q000032:analysis / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D010100:Oxygen / Q000378:metabolism; D011355:Prodrugs / Q000008:administration & dosage / Q000032:analysis / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013045:Species Specificity
D000970:Antineoplastic Agents; D020719:Glucuronides; D009588:Nitrogen Mustard Compounds; C522381:PR-104; C524170:PR-104A; D011355:Prodrugs; D005978:Glutathione; D010100:Oxygen; D000111:Acetylcysteine