Biotransformation of clozapine in humans

The metabolic pathways of clozapine (CZ, Clozaril (Novartis Pharmaceuticals Corporation, East Hanover, NJ), 8-chloro-11-(4-methyl-1-piperazinyl)-5H-dibenzo [b,e][1,4]diazepine, a tricyclic benzodiazepine neuroleptic which has a reduced risk of unwanted neurological effects, were determined in normal male volunteers after a single oral dose of 50 mg of [14C]CZ. There was no radio-activity in exhaled breath, and excretion of total radioactivity was approximately 50% in urine and 30% in feces; parent CZ was a minor component in the excreta. The metabolic profiles were determined in urine and feces using HPLC coupled with radioactivity monitoring. The major metabolic pathways were demethylation, oxidation of the aromatic ring in the 7- and 8-positions, and conjugation. The major urinary components were 8-hydroxy-deschloro-DCZ (desmethylCZ) and its glucuronide, 7-hydroxy-8-chloro-DCZ sulfate and CZ-NO (clozapine N-oxide). Minor amounts of CZ, 7-hydroxy-8-chloro-CZ glucuronide and DCZ were also present. In feces the major component was CZ-N-glucuronide. Urinary excretion of CZ-NO was more rapid than the products of aromatic ring hydroxylation and conjugation.