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

Abstract

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 [14C]VNP40101M to rats. A single 10 mg/kg IV bolus dose of [14C]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 [14C]laromustine was approximately 62 min and the peak plasma concentration (Cmax) averaged 8.3 μg/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 [14C]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. The predicted total body and target organ exposures for humans given a single 100μCi IV dose of [14C]VNP40101M were well within the medical guidelines for maximum radioactivity exposures in human subjects.