title: In vitro toxicity of clozapine, olanzapine, and quetiapine on granulocyte-macrophage progenitors (GM-CFU).
abstract: BACKGROUND
  Atypical antipsychotics may lead to agranulocytosis because of the apoptosis caused by cells binding nitrenium molecules. 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 analogues 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 microg/mL), followed by olanzapine (IC90 = 13.43 +/- 1.23 microg/mL), clozapine (IC90 = 44.71 +/- 4.42 microg/mL), and quetiapine (IC90 = 137.24 +/- 15.36 microg/mL).
  
  
  CONCLUSIONS
  These data agree with recent clinical 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 clinical 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.
authors.affiliation: Institute of Microbiology, University of Milan, Italy. augusto.pessina@unimi.it
authors.forename: A
authors.initials: A
authors.lastname: Pessina
authors.forename: E
authors.initials: E
authors.lastname: Turlizzi
authors.forename: A
authors.initials: A
authors.lastname: Bonomi
authors.forename: F
authors.initials: F
authors.lastname: Guizzardi
authors.forename: L
authors.initials: L
authors.lastname: Cavicchini
authors.forename: C
authors.initials: C
authors.lastname: Croera
authors.forename: S
authors.initials: S
authors.lastname: Bareggi
mesh_terms: D014150:Antipsychotic Agents / Q000494:pharmacology*; D001569:Benzodiazepines / Q000494:pharmacology; D002746:Chlorpromazine / Q000494:pharmacology; D003024:Clozapine / Q000494:pharmacology*; D003114:Colony-Forming Units Assay; D003987:Dibenzothiazepines / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006098:Granulocytes / Q000187:drug effects*; D006412:Hematopoietic Stem Cells / Q000187:drug effects*; D006801:Humans; D008264:Macrophages / Q000187:drug effects*; D000077152:Olanzapine; D000069348:Quetiapine Fumarate
chemical_list: D014150:Antipsychotic Agents; D003987:Dibenzothiazepines; D001569:Benzodiazepines; D000069348:Quetiapine Fumarate; D003024:Clozapine; D000077152:Olanzapine; D002746:Chlorpromazine