title: 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.affiliation: Department of Medicine, University Hospitals of Cleveland, Case Western Reserve University School of Medicine, Ohio.
authors.forename: S L
authors.initials: SL
authors.lastname: Gerson
authors.forename: C
authors.initials: C
authors.lastname: Arce
authors.forename: H Y
authors.initials: HY
authors.lastname: Meltzer
mesh_terms: D000380:Agranulocytosis / Q000097:blood / Q000139:chemically induced; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003024:Clozapine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D003114:Colony-Forming Units Assay; D004305:Dose-Response Relationship, Drug; D006410:Hematopoiesis / Q000187:drug effects*; D006412:Hematopoietic Stem Cells / Q000187:drug effects*; D006801:Humans
chemical_list: C058272:norclozapine; D003024:Clozapine