title: Isolation and identification of urinary metabolites of porfiromycin in dogs and humans.
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.
authors.affiliation: Department of Development, Vion Pharmaceuticals, Inc., New Haven, Connecticut, USA.
authors.forename: W
authors.initials: W
authors.lastname: Lang
authors.forename: J
authors.initials: J
authors.lastname: Mao
authors.forename: T W
authors.initials: TW
authors.lastname: Doyle
authors.forename: B
authors.initials: B
authors.lastname: Almassian
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000737:chemistry / Q000378:metabolism / Q000652:urine; D002851:Chromatography, High Pressure Liquid; D004285:Dogs; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D013058:Mass Spectrometry; D011160:Porfiromycin / Q000737:chemistry / Q000302:isolation & purification / Q000652:urine*; D019275:Radiopharmaceuticals / Q000737:chemistry / Q000302:isolation & purification / Q000652:urine*; D014316:Tritium
chemical_list: D000903:Antibiotics, Antineoplastic; D019275:Radiopharmaceuticals; D014316:Tritium; D011160:Porfiromycin