title: Effect of clozapine and olanzapine on neutrophil kinetics: implications for drug-induced agranulocytosis.
abstract: Clozapine is effective in the treatment of schizophrenia; however, its use is limited by a relatively high incidence of idiosyncratic agranulocytosis. The mechanism of clozapine-induced idiosyncratic agranulocytosis is unknown. Although most patients treated with clozapine do not develop agranulocytosis, most do have an immune response with an increase in inflammatory cytokines such as IL-6 and a release of immature neutrophils with neutrophilia rather than agranulocytosis. We have previously shown that treatment of rabbits with clozapine also causes an early release of neutrophils. Clozapine is oxidized to a reactive nitrenium ion that covalently binds to neutrophils, and this reactive metabolite may be responsible for the observed effects. Olanzapine and clozapine have very similar structures, and olanzapine is also oxidized to a reactive nitrenium ion; however, if it ever causes agranulocytosis, the incidence is much lower than that of clozapine. One possible basis for the difference in incidence of agranulocytosis between clozapine and olanzapine is that the therapeutic dose of olanzapine is much lower than that of clozapine. In this study, we compared the effects of clozapine and olanzapine in Sprague-Dawley rats at an equimolar dose and found that only clozapine had a significant effect on neutrophil kinetics. This suggests that the immune response and effects on neutrophil kinetics induced by clozapine are related to its ability to cause agranulocytosis.
authors: Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto , 144 College Street, Toronto, Ontario Canada M5S 3M2.
authors: Winnie
authors: W
authors: Ng
authors: Rossoune
authors: R
authors: Kennar
authors: Jack
authors: J
authors: Uetrecht
mesh_terms: D000380:Agranulocytosis / Q000139:chemically induced / Q000378:metabolism; D000818:Animals; D014150:Antipsychotic Agents / Q000009:adverse effects / Q000494:pharmacology*; D001569:Benzodiazepines / Q000009:adverse effects / Q000494:pharmacology*; D001853:Bone Marrow / Q000187:drug effects / Q000502:physiology; D003024:Clozapine / Q000009:adverse effects / Q000494:pharmacology*; D005260:Female; D005269:Femur; D007700:Kinetics; D007958:Leukocyte Count; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D000077152:Olanzapine; D017207:Rats, Sprague-Dawley; D013977:Tibia
chemical_list: D014150:Antipsychotic Agents; D001569:Benzodiazepines; D003024:Clozapine; D000077152:Olanzapine