TY - JOUR
T1 - N-desmethylclozapine
T2 - A clozapine metabolite that suppresses haemopoiesis
AU - Gerson, S. L.
AU - Arce, C.
AU - Meltzer, H. Y.
PY - 1994/1/1
Y1 - 1994/1/1
N2 - 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.
AB - 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.
KW - agranulocytosis
KW - clozapine
KW - drug-induced marrow suppression
KW - haemopoiesis
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U2 - 10.1111/j.1365-2141.1994.tb04786.x
DO - 10.1111/j.1365-2141.1994.tb04786.x
M3 - Article
C2 - 8043437
AN - SCOPUS:0028341606
VL - 86
SP - 555
EP - 561
JO - British Journal of Haematology
JF - British Journal of Haematology
SN - 0007-1048
IS - 3
ER -