N-DESMETHYLCLOZAPINE - A CLOZAPINE METABOLITE THAT SUPPRESSES HEMATOPOIESIS
N-DESMETHYLCLOZAPINE - A CLOZAPINE METABOLITE THAT SUPPRESSES HEMATOPOIESIS
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DOI：
10.1111/j.1365-2141.1994.tb04786.x
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发表时间：
1994-03-01
影响因子：
6.5
通讯作者：
MELTZER, HY
中科院分区：
文献类型：
--
作者：
GERSON, SL;ARCE, C;MELTZER, HY
氯氮平是一种新型抗精神病药物，对难治性精神分裂症特别有效，在大约0.8%的美国患者中引起病因不明的严重粒细胞缺乏症。我们评估了药物诱导的粒细胞缺乏症的潜在毒性机制。氯氮平，两个主要的代谢产物N-去甲基氯氮平和N-氧化物氯氮平，和其他五个氯氮平衍生物进行了筛选的毒性正常造血前体。除N-去甲基氯氮平外，所有化合物对CFU-GM、BFU-E和CFU-GEMM的毒性发生在浓度至少为未受影响患者报告的正常血清水平的10倍时。相反，N-去甲基氯氮平的LD（50）对CFU-GM为2.5 μ g/ml，对BFU-E为3.2 μ g/ml，对CFU-GEMM为2.4 μ g/ml，仅为正常血清浓度的3-6倍。急性氯氮平引起的粒细胞缺乏症患者的骨髓对氯氮平或N-去甲基氯氮平的敏感性并不比正常供体的骨髓高。这些研究表明，N-去甲基氯氮平，氯氮平的主要代谢产物，本身是有毒的，或进一步代谢为一种不稳定的化合物，这是有毒的骨髓和红系造血前体。
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-desmethylclozapine, 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 LD(50) for N-desmethylclozapine was 2.5 mu g/ml for CFU-GM, 3.2 mu g/ml for BFU-E, and 2.4 mu g/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.