RT Journal Article
SR Electronic
T1 Biotransformation of Clozapine in Humans
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 603
OP 609
VO 25
IS 5
A1 Jeremy G. Dain
A1 Joseph Nicoletti
A1 Frances Ballard
YR 1997
UL http://dmd.aspetjournals.org/content/25/5/603.abstract
AB 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 tricylic 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 radioactivity 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. The American Society for Pharmacology and Experimental Therapeutics