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 isomericN-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 cysteineS-conjugates in urine indicates that the metabolism of PM may be through GSH conjugation.
Footnotes
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Send reprint requests to: Bijan Almassian, Ph.D., Department of Development, Vion Pharmaceuticals, Inc., Four Science Park, New Haven, CT 06511. E-mail: balmassi{at}vionpharm.com
- Abbreviations used are::
- PM
- porfiromycin
- MC
- mitomycin C
- RP-HPLC
- reversed-phase high performance liquid chromatography
- LC/MS
- liquid chromatography/mass spectrometry
- APCI
- atmospheric pressure chemical ionization
- ESI-MS
- electrospray ionization-mass spectrometry
- RT
- retention time
- Received December 7, 1999.
- Accepted April 19, 2000.
- The American Society for Pharmacology and Experimental Therapeutics
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