Metabolism and Excretion of the Novel Bioreductive Prodrug PR-104 in Mice, Rats, Dogs, and Humans
In: Drug metabolism and disposition, Jg. 38 (2010), Heft 3, S. 498-508
academicJournal
- print, 3/4 p
Zugriff:
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 [3H]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-β-glucuronidation of PR-104A in dogs and humans than in rodents. The structure of the O-β-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.
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Metabolism and Excretion of the Novel Bioreductive Prodrug PR-104 in Mice, Rats, Dogs, and Humans
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Autor/in / Beteiligte Person: | YONGCHUAN, GU ; ATWELL, Graham J ; WILSON, William R |
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Zeitschrift: | Drug metabolism and disposition, Jg. 38 (2010), Heft 3, S. 498-508 |
Veröffentlichung: | Bethesda, MD: American Society for Pharmacology and Experimental Therapeutics, 2010 |
Medientyp: | academicJournal |
Umfang: | print, 3/4 p |
ISSN: | 0090-9556 (print) |
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