Metabolic disposition of the anti-cancer agent [¹⁴C]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 [¹⁴C]VNP40101M to rats. A single 10 mg/kg IV bolus dose of [¹⁴C]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 [¹⁴C]laromustine was approximately 62 min and the peak plasma concentration (C_max) 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 [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.

4. The predicted total body and target organ exposures for humans given a single 100 µCi IV dose of [¹⁴C]VNP40101M were well within the medical guidelines for maximum radioactivity exposures in human subjects.

• Anti-cancer agent
• mass balance
• quantitative whole-body autoradiography

Acknowledgements

This work was done at QPS for Vion Pharmaceuticals Inc. We would like to thanks Drs. Bruce Aungst and Eric Solon of QPS for supervising the studies.

Declaration of interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.