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
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.