HOMEPRODUCTSCOMPANYCONTACTFAQResearchDictionaryPharmaSign Up FREE or Login

Isolation and identification of metabolites of porfiromycin formed in the presence of a rat liver preparation.

Abstract
The isolation and identification of the major metabolites of porfiromycin formed in the presence of a rat liver preparation under aerobic conditions were performed with high-performance liquid chromatography and electrospray ionization mass spectrometry. Porfiromycin was extensively metabolized by the rat liver preparation in an aqueous 0.1 M potassium phosphate buffer (pH 7.4) containing an NADPH generating system at 37 degrees C. A total of eight metabolites was identified as mitosene analogs. Of these, three primary metabolites are 2-methylamino-7-aminomitosene, 1,2-cis and 1,2-trans-1-hydroxy-2-methylamino-7-aminomitosene, which are consistent with those previously observed in hypoxia using purified rat liver NADPH-cytochrome c reductase. Interestingly, 2-methylamino-7-aminomitosene is a reactive metabolite, which undergoes further activation at the C-10 position by the loss of carbamic acid and then links with the 7-amino group of the primary metabolites to yield two dimeric adducts. In addition, three phosphate adducts, 10-decarbamoyl-2-methylamino-7-aminomitosene-10-phosphate, 1,2-cis and 1,2-trans-2-methylamino-7-aminomitosene-1-phosphate, were also identified in the incubation system. The configurations of the diastereoisomeric metabolites were determined with (1)HNMR and phosphatase digestion. On the basis of the metabolite profile, we propose in vitro metabolic pathways for porfiromycin. The findings provide direct evidence for understanding the reactive nature and hepatic metabolism of the drug currently in phase III clinical trials.
AuthorsW Lang, J Mao, Q Wang, C Niu, T W Doyle, B Almassian
JournalJournal of pharmaceutical sciences (J Pharm Sci) Vol. 89 Issue 2 Pg. 191-8 (Feb 2000) ISSN: 0022-3549 [Print] United States
PMID10688748 (Publication Type: Journal Article)
CopyrightCopyright 2000 Wiley-Liss, Inc.
Chemical References
  • Antibiotics, Antineoplastic
  • Porfiromycin
  • Cysteine
  • Acetylcysteine
Topics
  • Acetylcysteine (metabolism)
  • Animals
  • Antibiotics, Antineoplastic (isolation & purification, metabolism)
  • Biotransformation
  • Chromatography, High Pressure Liquid
  • Cysteine (metabolism)
  • Liver (chemistry, metabolism)
  • Mass Spectrometry
  • Nuclear Magnetic Resonance, Biomolecular
  • Porfiromycin (isolation & purification, metabolism, pharmacokinetics)
  • Rats
  • Rats, Sprague-Dawley
  • Spectrophotometry, Ultraviolet

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research graph!


Choose Username:
Email:
Password:
Verify Password:
Enter Code Shown: