Abstract |
Porfiromycin (PM), a bioreductive alkylating agent, is currently under development for the treatment of head and neck cancers as an adjunct to radiation therapy in phase III clinical trials. After i.v. administration of a single dose of PM to patients at 40 mg/m2, urinary metabolites were isolated by HPLC and identified by atmospheric pressure chemical ionization mass spectrometry. In dogs, [methyl-3H]PM was administered i.v. to three Beagle dogs at a single dose of 2 mg/kg. Urinary excretion of radioactivity and PM at different times was determined by liquid scintillation counting and by HPLC, respectively. An average of 48.0% of total radioactivity given to the dogs was cumulatively excreted in urine over a period of 7 days. Unchanged parent drug excreted in urine accounted for 10.8% of the administered dose over the same period of time. The results indicated that the majority of excreted dose in dog urine was in the form of metabolites. Three phase I and four phase II metabolites of PM were identified in human and dog urine. The phase I metabolites are 2-methylamino-7-aminomitosene, 1,2-cis and 1,2-trans-1-hydroxy-2-methylamino-7-aminomitosenes. The phase II metabolites are a pair of isomeric N-acetylcysteine S-conjugates and a pair of isomeric cysteine S-conjugates of mitosenes at the C-1 and C-10 positions. Most of the identified metabolites were confirmed by comparison with synthetic reference standards using HPLC and liquid chromatography/mass spectrometry (LC/MS). The identification of mercapturic acids and cysteine S-conjugates in urine indicates that the metabolism of PM may be through GSH conjugation.
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Authors | W Lang, J Mao, T W Doyle, B Almassian |
Journal | Drug metabolism and disposition: the biological fate of chemicals
(Drug Metab Dispos)
Vol. 28
Issue 8
Pg. 899-904
(Aug 2000)
ISSN: 0090-9556 [Print] United States |
PMID | 10901698
(Publication Type: Journal Article)
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Chemical References |
- Antibiotics, Antineoplastic
- Radiopharmaceuticals
- Tritium
- Porfiromycin
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Topics |
- Animals
- Antibiotics, Antineoplastic
(chemistry, metabolism, urine)
- Chromatography, High Pressure Liquid
- Dogs
- Humans
- Magnetic Resonance Spectroscopy
- Male
- Mass Spectrometry
- Porfiromycin
(chemistry, isolation & purification, urine)
- Radiopharmaceuticals
(chemistry, isolation & purification, urine)
- Tritium
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