N-desmethylclozapine: a clozapine metabolite that suppresses haemopoiesis.

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 micrograms/ml for CFU-GM, 3.2 micrograms/ml for BFU-E, and 2.4 micrograms/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.

• Authors: S L Gerson, C Arce, H Y Meltzer
• Journal: British journal of haematology (Br J Haematol) Vol. 86 Issue 3 Pg. 555-61 (Mar 1994) ISSN: 0007-1048 [Print] England
• PMID: 8043437 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• norclozapine
• Clozapine

Topics

• Agranulocytosis (blood, chemically induced)
• Cell Survival (drug effects)
• Cells, Cultured
• Clozapine (adverse effects, analogs & derivatives, chemistry, metabolism, pharmacology)
• Colony-Forming Units Assay
• Dose-Response Relationship, Drug
• Hematopoiesis (drug effects)
• Hematopoietic Stem Cells (drug effects)
• Humans