In vivo metabolism of norbormide in rats and mice

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.