Metabolism and excretion of the novel bioreductive prodrug PR-104 in mice, rats, dogs, and humans

Show simple item record Gu, Yongchuan en Atwell, Graham en Wilson, William en 2012-05-24T22:51:57Z en 2010-03 en
dc.identifier.citation DRUG METABOLISM AND DISPOSITION 38(3):498-508 01 Mar 2010 en
dc.identifier.issn 0090-9556 en
dc.identifier.uri en
dc.description.abstract 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 (PR104G) 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. en
dc.language English en
dc.publisher The American Society for Pharmacology and Experimental Therapeutics en
dc.relation.ispartofseries Drug Metabolism and Disposition en
dc.rights Items in ResearchSpace are protected by copyright, with all rights reserved, unless otherwise indicated. Previously published items are made available in accordance with the copyright policy of the publisher. en
dc.rights.uri en
dc.subject Science & Technology en
dc.subject Life Sciences & Biomedicine en
dc.subject Pharmacology & Pharmacy en
dc.subject MUSTARD GROUP en
dc.subject TUMOR-CELLS en
dc.subject CROSS-LINKS en
dc.subject HYPOXIA en
dc.subject IFOSFAMIDE en
dc.subject DRUGS en
dc.title Metabolism and excretion of the novel bioreductive prodrug PR-104 in mice, rats, dogs, and humans en
dc.type Journal Article en
dc.identifier.doi 10.1124/dmd.109.030973 en
pubs.issue 3 en
pubs.begin-page 498 en
pubs.volume 38 en
dc.rights.holder Copyright: The American Society for Pharmacology and Experimental Therapeutics en
dc.identifier.pmid 20019245 en en
pubs.end-page 508 en
dc.rights.accessrights en
pubs.subtype Article en
pubs.elements-id 118820 en Medical and Health Sciences en Medical Sciences en Auckland Cancer Research en Science en Science Research en Maurice Wilkins Centre (2010-2014) en
dc.identifier.eissn 1521-009X en
pubs.record-created-at-source-date 2012-05-25 en
pubs.dimensions-id 20019245 en

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