N-desmethylclozapine: A clozapine metabolite that suppresses haemopoiesis

S. L. Gerson*, C. Arce, H. Y. Meltzer

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

94 Scopus citations

Abstract

Clozapine, a novel antipsychotic drug that is particularly effective in treatment-resistant schizophrenia, causes severe agranulocytosis of unknown aetiology in approximately 0.8% of U.S. patients. We evaluated potential toxic mechanisms of drug-induced agranulocytosis. Clozapine, the two major metabolites N-desmethylclozapine and N-oxide clozapine, and five other clozapine derivatives were screened for toxicity to normal haemopoietic precursors. For all compounds except N-des-methylclozapine, toxicity to CFU- GM, BFU-E and CFU-GEMM occurred at concentrations at least 10 times the normal serum levels reported in unaffected patients. In contrast, the LD50 for N-desmethylclozapine was 2.5 μg/ml for CFU-GM, 3.2 μg/ml for BFU-E, and 2.4 μg/ml for CFU-GEMM, only 3-6 times the normal serum concentration. Bone marrow from patients with acute clozapine-induced agranulocytosis was not more sensitive to clozapine or N-desmethylclozapine than bone marrow from normal donors. These studies suggest that N-desmethylclozapine, the major metabolite of clozapine, is itself toxic or is further metabolized to an unstable compound which is toxic to haemopoietic precursors of both myeloid and erythroid lineages.

Original languageEnglish (US)
Pages (from-to)555-561
Number of pages7
JournalBritish Journal of Haematology
Volume86
Issue number3
DOIs
StatePublished - Jan 1 1994

Keywords

  • agranulocytosis
  • clozapine
  • drug-induced marrow suppression
  • haemopoiesis

ASJC Scopus subject areas

  • Hematology

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