norclozapine and Agranulocytosis

Clozapine may produce agranulocytosis in 1-2% of patients treated with it for 4 weeks or longer. Three mechanisms have been suggested: a direct toxic effect of metabolite of clozapine, an immunologic mechanism or a combination of both. N-desmethylclozapine, the major metabolite of clozapine, has been reported to be more toxic than clozapine itself (Gerson et al., 1994). In this study, plasma levels of clozapine and desmethylclozapine were measured in five patients who developed agranulocytosis. The levels of both parent compound and metabolite were within the range found in other patients and below the toxic range. If a toxic mechanism is involved in clozapine-induced agranulocytosis, an additional vulnerability factor must be important.

Topics: Adult; Agranulocytosis; Clozapine; Female; Humans; Male; Schizophrenia

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.

Topics: Agranulocytosis; Cell Survival; Cells, Cultured; Clozapine; Colony-Forming Units Assay; Dose-Response Relationship, Drug; Hematopoiesis; Hematopoietic Stem Cells; Humans