Identification of urinary metabolites of clemastine after oral administration to man

Abstract

The metabolism of clemastine, 2-{2-[1-(4-chlorophenyl)-1-phenylethoxy]ethyl}-1-methylpyrrolidine, has been studied in three adult male volunteers after a single oral dose of 20 mg as the fumarate. After enzymatic hydrolysis solvent extracts of urine were derivatized with N-methyl-N-trimethylsilyltrifluoroacetamide-ammonium iodide and analysed by gas chromatography-mass spectrometry. The structures of metabolites were determined on the basis of electron impact and chemical ionization mass spectra and the identities of some (e.g. carbinol, 4-chlorobenzophenone and 4-chlorophenylstyrene) were confirmed by use of authentic standards. The principal route of metabolism of clemastine in man involves direct oxidation, O-dealkylation (fission of the ether bond), aromatic hydroxylation, aliphatic oxidation, alcoholic dehydration, and then enzymatic hydrolysis. Of the total amount of metabolites excreted in the urine 35% was carbinol (metabolite M3, major metabolite), 15% was M1, 17% was M2, 11% was M4, 9% was M5, 8% was M6 and 5% was M7.