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0090-9556/97/2505-0603-0609$02.00/0
DRUG METABOLISM AND DISPOSITION
Copyright © 1997 by The American Society for Pharmacology and Experimental Therapeutics
Vol. 25, No. 5

Biotransformation of Clozapine in Humans

Jeremy G. Dain, Joseph Nicoletti, and Frances Ballard

Drug Metabolism and Pharmacokinetics Department, Novartis Pharmaceuticals Corporation

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.

Copyright © 1997 by The American Society for Pharmacology and Experimental Therapeutics


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Copyright © 1997 by the American Society for Pharmacology and Experimental Therapeutics.