In vitro toxicity of clozapine, olanzapine, and quetiapine on granulocyte-macrophage progenitors (GM-CFU)

Introduction: Atypical antipsychotics may lead to agranulocytosis because of the apoptosis caused by cells binding nitrenium mols. Studies showing the direct myelotoxicity of clozapine were undertaken years ago using different assays, and thus it is difficult to compare them with those of clozapine's analogs that have been more recently reported as causing neutropenia, agranulocytosis, and thrombocytopenia. Methods: We compared the direct toxicity of clozapine, olanzapine, quetiapine, and chlorpromazine using a previously standardized GM-CFU assay validated for predicting neutropenia. Results: The results showed that all of the drugs were characterized by dose-dependent toxicity, which was greatest in the case of chlorpromazine (IC90= 10.02 +- 0.69 mg/mL), followed by olanzapine (IC90= 13.43 +- 1.23 mg/mL), clozapine (IC90= 44.71 +- 4.42 mg/mL), and quetiapine (IC90= 137.24 +- 15.36 mg/mL). Discussion: These data agree with recent clin. reports concerning the direct or mediated toxic effects of olanzapine on progenitor and committed cells (GM-CFU) and suggest that the correlation between its plasma levels and clin. effects warrants further investigation. There are no published data concerning the bone marrow pharmacokinetics of atypical antipsychotics or their possible bioactivation by the bone marrow cell compartment, but our findings suggest that they may affect hematopoiesis in different ways, such as the direct action of them or their metabolites due to bioactivation by hematopoietic cells themselves.