Species differences in the disposition and metabolism of 1-methyl-3-(3-pyridyl)-5-(2-hydroxy-methylphenyl)-1h-1,2,4-triazole, a potential sedative-hypnotic compound

Abstract

1. Disposition and metabolism of 1-methyl-3-(3-pyridyl)-5-(2-hydroxy-methylphenyl)-1H-1,2,4-triazole, a new sedative-hypnotic, were studied in rats (i.v. and p.o.), cats (i.v.) and human volunteers (p.o.) with ¹⁴C-labelled drug.

2. In rat and man, the compound is well absorbed, extensively metabolized, and excreted mostly through the kidney; it has short plasma half-lives, 0–6 h in rat, 0.9 h in man, and 1.9 h in cat.

3. In rat and man metabolism involves N-oxidation of the pyridine ring (Metabolite I), and in cat oxidation of the hydroxymethyl group (Metabolite II). Four other conjugated metabolites (III-VI) isolated from rat urine and bile, and from urine of cats and man, have been characterized.

4. The unchanged compound, but not its metabolites, crosses the blood-brain barrier in rat and cat.

5. The species differences in the disposition and metabolism of the compound are consistent with previous pharmacological data indicating a greater and more prolonged effect in cat.