Potential Role of a Quetiapine Metabolite in Quetiapine-Induced Neutropenia and Agranulocytosis

Clozapine was the first of the atypical antipsychotics to be developed, but its use has been restricted because of toxicity issues, particularly the risk of potentially life-threatening drug-induced neutropenia and agranulocytosis, which occurs in about 1% of patients. Bioactivation of clozapine by peroxidases forms a reactive nitrenium ion, which covalently adducts to protein and leads to neutrophil toxicity. The current generation of clozapine-inspired atypical antipsychotics has reduced toxicity through improved potency/decreased dose or through structural modification to prevent peroxidase-catalyzed nitrenium ion formation. Through the substitution of sulfur for the bridging nitrogen found in clozapine, quetiapine does not directly form a nitrenium ion when incubated with myeloperoxidase/H2O2. We present evidence that cytochrome P450 2D6 catalyzes the formation of 7-hydroxyquetiapine, which can be oxidized by human myeloperoxidase to form a reactive quinone-imine and a reactive radical, which may acco...