Evaluation of the absorption, excretion and metabolism of [14 C] etoperidone in man

Abstract

1. The absorption, excretion and metabolism of 2-{3-[4-(3-chlorophenyl)-1-piperazinyl]propyl}-4,5-diethyl-2,4-dihydro-3H-1,2,4 hydrochloride (etoperidone HCl) was investigated in six healthy men. Subjects were fasted overnight before receiving a single oral dose of a 100mg solution [14C] etoperidone HCl. 2. Plasma (0-48h), urine (0-120h) and faecal (0-120h) samples were collected. The terminal half-life of the total radioactivity from plasma was 21.7 ± 2.8 h with an apparent clearance of 1.01 ± 0.08 ml min-1. Recoveries of total radioactivity in urine and faeces were 78.8 ± 3.6% and 9.6 ± 4.1% of the dose, respectively. 3. Etoperidone and 21 metabolites were isolated and identified in the plasma, urine and faecal extracts. Unchanged etoperidone accounted for <0.01% of the dose in all excreta samples. Nine metabolites were identified in the plasma extracts and 21 urinary metabolites were identified. Seven faecal metabolites were identified. 4. Five proposed pathways were used to describe the formation of the metabolites: alkyl oxidation, piperazinyl oxidation, N -dealkylation, phenyl hydroxylation and conjugation. Alkyl oxidation of etoperidone resulted in the formation of 2-{3-[4-(3- chlorophenyl)-1-piperazinyl]propyl}-4-ethyl-2,4-dihydro-5-(1-hydroxyethyl)-3H-1 triazole-3-one. Piperazinyl oxidation of this metabolite leads to the formation of its N -oxide. N -dealkylation of the piperazinyl group led to the formation of 1-(3-chlorophenyl) piperazine and triazole propionic acid. Phenyl hydroxylation led to three important metabolites in the urine and faeces.