In vivo metabolism of norbormide in rats and mice

Environmental Toxicology and Pharmacology
Shanthinie RavindranMalcolm Tingle

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.

References

Jan 1, 1970·Annual Review of Pharmacology·H B Hucker
Mar 1, 1996·British Journal of Pharmacology·Sergio BovaGabriella Cargnelli
Dec 1, 1996·Environmental Health Perspectives·R F Henderson
Apr 24, 1964·Science·A P RoszkowskiR J Mohrbacher
Apr 1, 1965·Journal - Forensic Science Society·R U RUSSELL
Jun 15, 2005·Biochimica Et Biophysica Acta·Fernanda RicchelliSergio Bova
May 19, 2007·Biochimica Et Biophysica Acta·Alessandra ZulianFernanda Ricchelli
Jan 1, 2009·Environmental Toxicology and Pharmacology·Shanthinie RavindranMalcolm Tingle

Citations

Oct 8, 2017·Drug Testing and Analysis·Carina de Souza AnselmoFrancisco Radler de Aquino Neto

Related Concepts

Blood
Liver
Metabolism
Laboratory mice
Norbormide
Oral Cavity
Receptor, Muscarinic M3
Intravenous
Toxic Effect
Metabolite

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