In vivo metabolism of norbormide in rats and mice

Shanthinie Ravindran; Brian Hopkins; Sergio Bova; Malcolm Tingle

doi:10.1016/j.etap.2009.03.013

In vivo metabolism of norbormide in rats and mice

Environ Toxicol Pharmacol. 2009 Jul;28(1):147-51. doi: 10.1016/j.etap.2009.03.013. Epub 2009 Apr 8.

Authors

Shanthinie Ravindran¹, Brian Hopkins, Sergio Bova, Malcolm Tingle

Affiliation

¹ Department of Pharmacology and Clinical Pharmacology, The University of Auckland, Private Bag 92019, Auckland, New Zealand; Landcare Research, Private Bag 92170, Auckland 1142, New Zealand.

PMID: 21783995
DOI: 10.1016/j.etap.2009.03.013

Abstract

Norbormide's species-selective lethality displays 150-fold and 40-fold more sensitivity to rats than mice and guinea pigs, respectively. Our previous study revealed marked inter-species differences in rate and route of metabolism in liver preparations from different species, with hydroxylation the major route. To examine whether rapid metabolic clearance or species-dependent formation of a toxic metabolite play a role in the marked species-sensitivity, we initiated in vivo metabolic studies in rats and mice. After oral dosing, norbormide was detected in mouse but not rat blood. In contrast, liver analysis revealed that norbormide concentration was significantly higher in rat compared with mouse, and that it underwent extensive metabolism tentatively identified via hydroxylation in rat, whilst none was detected in mouse. Although an unidentified metabolite (M3) was detected in rat blood after oral dosing, no metabolites were detected 1min after intravenous dosing, which proved lethal at 0.5mg/kg. Taken together, the data indicate that the toxicity resides with the parent compound, rather species-dependent formation of a potent metabolite and that species sensitivity may be controlled at the pharmacodynamic level.