Biotransformation and Rearrangement of Laromustine

Details

• Personal Author:
  King I ; Nassar A-EF ; Wisnewski AV
• Description:
  This review highlights the recent research into the biotransformations and rearrangement of the sulfonylhydrazine-alkylating agent laromustine. Incubation of [14C]laromustine with rat, dog, monkey, and human liver microsomes produced eight radioactive components (C-1 to C-8). There was little difference in the metabolite profile among the species examined, partly because NADPH was not required for the formation of most components, which instead involved decomposition and/or hydrolysis. The exception was C-7, a hydroxylated metabolite, largely formed by CYP2B6 and CYP3A4/5. Liquid chromatography-multistage mass spectrometry (LC-MSn) studies determined that collision-induced dissociation, and not biotransformation or enzyme catalysis, produced the unique mass spectral rearrangement. Accurate mass measurements performed with a Fourier-transform ion cyclotron resonance mass spectrometer (FTICR-MS) significantly aided determination of the elemental compositions of the fragments and in the case of laromustine revealed the possibility of rearrangement. Further, collision-induced dissociation produced the loss of nitrogen (N2) and methylsulfonyl and methyl isocyanate moieties. The rearrangement, metabolite/decomposition products, and conjugation reactions were analyzed utilizing hydrogen-deuterium exchange, exact mass, 13C-labeled laromustine, nuclear magnetic resonance spectroscopy (NMR), and LC-MSn experiments to assist with the assignments of these fragments and possible mechanistic rearrangement. Such techniques produced valuable insights into these functions: 1) Cytochrome P450 is involved in C-7 formation but plays little or no role in the conversion of [14C]laromustine to C-1 through C-6 and C-8; 2) the relative abundance of individual degradation/metabolite products was not species-dependent; and 3) laromustine produces several reactive intermediates that may produce the toxicities seen in the clinical trials. [Description provided by NIOSH]
• Subjects:
  Biopharmaceutics Energy Metabolism Occupational Health Safety
• Keywords:
  Alkylating Agents Biological Effects Biotransformation Metabolism Pharmaceuticals Pharmacology
• ISSN:
  0090-9556
• Document Type:
  Text
• Funding:
  Grant
• Genre:
  Journal Article
• Place as Subject:
  Connecticut ; Delaware ; OSHA Region 1 ; OSHA Region 3
• CIO:
  National Institute for Occupational Safety and Health (NIOSH)
• Topic:
  Workplace Safety & Health
• Location:
  North America
• Volume:
  44
• Issue:
  8
• NIOSHTIC Number:
  nn:20059506
• Citation:
  Drug Metab Dispos 2016 Aug; 44(8):1349-1363
• Contact Point Address:
  Dr. Ala F. Nassar, Yale University, School of Medicine, 300 Cedar St/TAC s416, New Haven, CT 06510
• Email:
  ala.nassar@yale.edu
• CAS Registry Number:
  Laromustine (CAS RN 173424-77-6)
• Federal Fiscal Year:
  2016
• Performing Organization:
  Yale University, New Haven, Connecticut
• Peer Reviewed:
  True
• Start Date:
  20130901
• Source Full Name:
  Drug Metabolism and Disposition
• End Date:
  20160831
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:8c45e593ee614659721d8ab07a817b269bbdfde1aa3aab17ef50b383dfe3c4cc2b679456fadec7cc730c9927f10e4934fb75980fa3665651c9fd3b7a08324d83
• Download URL:
  https://stacks.cdc.gov/view/cdc/223706/cdc_223706_DS1.pdf
• File Type:
  [PDF - 1.80 MB ]