Metabolic disposition of the anti-cancer agent [(14)C]laromustine in male rats

Details

• Personal Author:
  King I ; Nassar AF ; Wisnewski A
• Description:
  Laromustine (VNP40101M, also known as Cloretazine) is a novel sulfonylhydrazine alkylating (anticancer) agent. This article describes the use of quantitative whole-body autoradiography (QWBA) and mass balance to study the tissue distribution, the excretion mass balance and pharmacokinetics after intravenous administration of [(14)C]VNP40101M to rats. A single 10 mg/kg IV bolus dose of [(14)C]VNP40101M was given to rats. The recovery of radioactivity from the Group 1 animals over a 7-day period was an average of 92.1% of the administered dose, which was accounted for in the excreta and carcass. Most of the radioactivity was eliminated within 48 h via urine (48%), with less excreted in feces (5%) and expired air accounted for (11%). The plasma half-life of [(14)C]laromustine was approximately 62 min and the peak plasma concentration (Cmax) averaged 8.3 ug/mL. The QWBA study indicated that the drug-derived radioactivity was widely distributed to tissues through 7 days post-dose after a single 10 mg/kg IV bolus dose of [(14)C]VNP40101M to male pigmented Long-Evans rats. The maximum concentrations were observed at 0.5 or 1 h post-dose for majority tissues (28 of 42). The highest concentrations of radioactivity were found in the small intestine contents at 0.5 h (112.137 ug equiv/g), urinary bladder contents at 3 h (89.636 ug equiv/g) and probably reflect excretion of drug and metabolites. The highest concentrations in specific organs were found in the renal cortex at 1 h (28.582 ug equiv/g), small intestine at 3 h (16.946 ug equiv/g), Harderian gland at 3 h (12.332 ug equiv/g) and pancreas at 3 h (12.635 ug equiv/g). Concentrations in the cerebrum (1.978 ug equiv/g), cerebellum (2.109 ug equiv/g), medulla (1.797 ug equiv/g) and spinal cord (1.510 ug equiv/g) were maximal at 0.5 h post-dose and persisted for 7 days. The predicted total body and target organ exposures for humans given a single 100 uCi IV dose of [(14)C]VNP40101M were well within the medical guidelines for maximum radioactivity exposures in human subjects. [Description provided by NIOSH]
• Subjects:
  Animals Biopharmaceutics Energy Metabolism Laboratories Occupational Health Safety
• Keywords:
  Animal Studies Antineoplastic Agents Author Keywords: Anti-cancer Agent Laboratory Animals Mass Balance Metabolic Rate Metabolic Study Metabolism Pharmaceuticals Quantitative Whole-body Autoradiography
• ISSN:
  0049-8254
• Document Type:
  Text
• Funding:
  Grant
• Genre:
  Journal Article
• Place as Subject:
  Connecticut ; OSHA Region 1
• CIO:
  National Institute for Occupational Safety and Health (NIOSH)
• Topic:
  Workplace Safety & Health
• Location:
  North America
• Volume:
  45
• Issue:
  8
• NIOSHTIC Number:
  nn:20047765
• Citation:
  Xenobiotica 2015 Aug; 45(8):711-721
• Contact Point Address:
  Dr. Ala F. Nassar, PhD, Department of Internal Medicine, Yale University, New Haven, CT, USA
• Email:
  ala.nassar@yale.edu
• CAS Registry Number:
  Laromustine (CAS RN 173424-77-6)
• Federal Fiscal Year:
  2015
• Performing Organization:
  Yale University, New Haven, Connecticut
• Peer Reviewed:
  True
• Start Date:
  20130901
• Source Full Name:
  Xenobiotica
• End Date:
  20160831
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:dabf71cd120c192e4b9dea031d6067dc5e8dfe752753848fe591dc074a8535dda12e4d801ee57fc7b3f8eae218cc96e281352f76b4832d5718c3e38fa8c11070
• Download URL:
  https://stacks.cdc.gov/view/cdc/202751/cdc_202751_DS1.pdf
• File Type:
  [PDF - 1.12 MB ]