The metabolism of nafimidone hydrochloride in the dog, primates and man

Abstract

1. The biotransformation of nafimidone, an imidazole-substituted anticonvulsant, has been studied by characterization of urinary metabolites in dogs, cynomolgus monkeys, baboons and man.

2. The biotransformation of nafimidone in these laboratory animals and man is initially very similar, in each case proceeding by reduction to the aliphatic alcohol metabolite, nafimidone alcohol or 1-[2-hydroxy-2-(2-naphthyl)ethyl]imidazole.

3. Further transformation of this metabolite involves oxidation in the naphthyl and imidazole functions, and/or conjugation.

4. The dog differs from the higher primates in that no metabolic modification of the naphthyl group takes place, the major metabolite in the dog being the O-β-glucuronide of nafimidone alcohol.

5. In higher primates and man two isomers involving dihydroxylation in the naphthyl ring—1-[2-hydroxy-2-(5,6- or 7,8-dihydroxydihydro-2-naphthyl)ethyl]imidazole—were tentatively identified. These species alone showed evidence of an imidazole linked N-glucuronide of nafimidone alcohol.

6. The possible occurrence of stereoselective metabolism by the introduction of a chiral centre at C-9 in nafimidone alcohol was indicated in human urine by the presence of both epimers of the O-β-glucuronide of nafimidone alcohol in a 2:1 ratio.