The biotransformation of nikethamide in the rat and its acceleration by hexachlorocyclohexane

1. Nicotinic acid monoethylamide, nicotinamide, and nikethamide-N-oxide have been identified, by cocrystallization with authentic carriers, as major products of the biotransformation of tritiated nikethamide in the rat. Nicotinic acid appears to be a minor metabolite of the analeptic in this species. 2. Both N-desalkylation and N-oxidation of nikethamide are enhanced in rats given 200 mg/kg of alpha-hexachlorocyclohexane once i.p. The beta- and gamma-isomers of hexachlorocyclohexane, when tested for their effect on the capacity of rat liver to desethylate the analeptic in vitro, have been found to be as affective as the alpha-isomer. 3. A convulsive dose of nikethamide given i.p. is shown to become ineffective in rats pretreated with alpha-hexachlorocyclohexane primarily as a consequence of accelerated biotransformation of the analeptic. 4. Rats can be made tolerant of nikethamide by daily injection of a convulsive dose of the drug for four to five days. Such animals metabolize ³H-nikethamide faster than non-tolerant controls.