THE METABOLIC FORMATION OF REACTIVE INTERMEDIATES FROM CLOZAPINE, A DRUG-ASSOCIATED WITH AGRANULOCYTOSIS IN MAN

Citation
Jl. Maggs et al., THE METABOLIC FORMATION OF REACTIVE INTERMEDIATES FROM CLOZAPINE, A DRUG-ASSOCIATED WITH AGRANULOCYTOSIS IN MAN, The Journal of pharmacology and experimental therapeutics, 275(3), 1995, pp. 1463-1475
Citations number
50
Categorie Soggetti
Pharmacology & Pharmacy
ISSN journal
00223565
Volume
275
Issue
3
Year of publication
1995
Pages
1463 - 1475
Database
ISI
SICI code
0022-3565(1995)275:3<1463:TMFORI>2.0.ZU;2-6
Abstract
Clozapine, a dibenzodiazepine antipsychotic, is associated with a 0.8% incidence of agranulocytosis. This clinically restrictive toxicity ha s been attributed to its chemically reactive metabolites. The generati on of such metabolites-assessed via covalent binding and formation of thioether adducts-was investigated using human, rat and mouse liver mi crosomes and human neutrophils and bone marrow cells, In every instanc e, one major glutathione adduct of clozapine-C-6 glutathionyl clozapin e- was formed in the presence of added glutathione. Adduct formation b y the neutrophils and myeloid cells was dependent on cell activation b y phorbol myristate acetate, Small fractions of drug underwent covalen t binding to microsomes (1-6.8%) and to protein coincubated with neutr ophils (0.47%) and myeloid cells (0.21%). Clozapine did not deplete in tracellular glutathione in activated neutrophils. Clozapine was also m etabolized in vivo to glutathione conjugates in rats and mice, the con jugates eliminated in bile over a 3-hr period representing 38% and 33% of the dose, respectively. in addition to the principal clozapine add uct found in vitro, the C-8 glutathionyl derivative of deschloroclozap ine was excreted by both species. it is concluded that clozapine under goes bioactivation in several tissues and considerable bioactivation i n vivo. The reactive metabolites generated by neutrophils and myeloid cells may play an important role in the metabolic causation of clozapi ne-induced agranulocytosis.