title: Metabolic disposition of the anti-cancer agent [(14)C]laromustine in male rats.
abstract: 1. 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. 2. 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 μg/mL. 3. 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 µg equiv/g), urinary bladder contents at 3 h (89.636 µg 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 µg equiv/g), small intestine at 3 h (16.946 µg equiv/g), Harderian gland at 3 h (12.332 µg equiv/g) and pancreas at 3 h (12.635 µg equiv/g). Concentrations in the cerebrum (1.978 µg equiv/g), cerebellum (2.109 µg equiv/g), medulla (1.797 µg equiv/g) and spinal cord (1.510 µg equiv/g) were maximal at 0.5 h post-dose and persisted for 7 days. 4. The predicted total body and target organ exposures for humans given a single 100 µCi IV dose of [(14)C]VNP40101M were well within the medical guidelines for maximum radioactivity exposures in human subjects.
authors: Department of Internal Medicine, School of Medicine, Yale University , New Haven, CT , USA .
authors: Ala F
authors: AF
authors: Nassar
authors: Adam
authors: A
authors: Wisnewski
authors: Ivan
authors: I
authors: King
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D006801:Humans; D006834:Hydrazines / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D007275:Injections, Intravenous; D008297:Male; D008665:Metalloporphyrins / Q000737:chemistry*; D023421:Models, Animal; D009369:Neoplasms / Q000188:drug therapy*; D051381:Rats; D020318:Rats, Long-Evans; D017207:Rats, Sprague-Dawley; D013449:Sulfonamides / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D014018:Tissue Distribution
chemical_list: D000970:Antineoplastic Agents; D006834:Hydrazines; D008665:Metalloporphyrins; D013449:Sulfonamides; C446505:iron chlorin e(6); C483604:laromustine
keywords: Anti-cancer agent; mass balance; quantitative whole-body autoradiography