dc.contributor.author |
Gu, Yongchuan |
en |
dc.contributor.author |
Atwell, Graham |
en |
dc.contributor.author |
Wilson, William |
en |
dc.date.accessioned |
2012-05-24T22:51:57Z |
en |
dc.date.issued |
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 |
http://hdl.handle.net/2292/18396 |
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 |
https://researchspace.auckland.ac.nz/docs/uoa-docs/rights.htm |
en |
dc.subject |
Science & Technology |
en |
dc.subject |
Life Sciences & Biomedicine |
en |
dc.subject |
Pharmacology & Pharmacy |
en |
dc.subject |
SELECTIVE TOXICITY |
en |
dc.subject |
ANTITUMOR-ACTIVITY |
en |
dc.subject |
MASS-SPECTROMETRY |
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.subject |
CHLOROACETALDEHYDE |
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 |
pubs.author-url |
http://dmd.aspetjournals.org/content/38/3/498 |
en |
pubs.end-page |
508 |
en |
dc.rights.accessrights |
http://purl.org/eprint/accessRights/RestrictedAccess |
en |
pubs.subtype |
Article |
en |
pubs.elements-id |
118820 |
en |
pubs.org-id |
Medical and Health Sciences |
en |
pubs.org-id |
Medical Sciences |
en |
pubs.org-id |
Auckland Cancer Research |
en |
pubs.org-id |
Science |
en |
pubs.org-id |
Science Research |
en |
pubs.org-id |
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 |