氯氮平代谢物的细胞毒性：对预测氯氮平诱导的粒细胞缺乏症的意义。

The cytotoxicity of clozapine metabolites: implications for predicting clozapine-induced agranulocytosis.

作者信息

Tschen A C, Rieder M J, Oyewumi L K, Freeman D J

机构信息

Department of Medicine, John P. Robarts Research Institute, University of Western Ontario, London, Canada.

出版信息

Clin Pharmacol Ther. 1999 May;65(5):526-32. doi: 10.1016/S0009-9236(99)70072-X.

DOI:10.1016/S0009-9236(99)70072-X

PMID:10340918

Abstract

BACKGROUND

Therapy of schizophrenia with clozapine is associated with the unpredictable development of severe neutropenia and agranulocytosis in 1% to 2% of patients. The mechanism of this effect is unknown but may involve reactive products of clozapine generated by either hepatic metabolism or oxidation by the peroxidase-peroxide system of activated neutrophils.

METHODS

Involvement of reactive metabolites was tested with in vitro cytotoxicity assays with use of peripheral blood mononuclear cells isolated from 3 groups of subjects: normal control subjects, patients with schizophrenia who tolerated clozapine therapy (control patients), and patients with schizophrenia in whom agranulocytosis developed while taking clozapine (patients with agranulocytosis). Cell viability was determined after incubations with clozapine and rat liver microsomes or clozapine and horseradish peroxidase-peroxide (HRP-H2O2).

RESULTS

In microsomal incubations, clozapine significantly increased the cell death in all groups: control subjects (8.8%+/-1.6%), control patients (7.4%+/-0.4%), and patients with agranulocytosis (9.1%+/-1.5%). However, differences between mean values were not statistically significant. In similar incubations with HRP-H2O2, clozapine significantly increased toxicity (P < .05) in cells from patients with agranulocytosis (22%+/-4.6%) compared with those from normal control subjects (7.7%+/-4.1%) or control patients (6.5%+/-4.4%).

CONCLUSIONS

These results suggest that both generating systems metabolized clozapine to toxic products. Some products may play a role in clozapine-induced agranulocytosis. Of diagnostic relevance is the observation the HRP-H2O2 produces significantly greater toxicity in cells from patients with agranulocytosis than in cells from control patients. Although the exact mechanism(s) of drug activation in vivo remains unclear, the bioactivation of clozapine by HRP-H2O2 may be a useful in vitro tool for predicting which patients are at risk for agranulocytosis before initiation of therapy.

摘要

背景

氯氮平治疗精神分裂症时，1%至2%的患者会出现严重中性粒细胞减少和粒细胞缺乏症，且这种情况发展不可预测。这种效应的机制尚不清楚，但可能涉及肝脏代谢产生的氯氮平反应产物，或活化中性粒细胞的过氧化物酶 - 过氧化物系统氧化产生的产物。

方法

使用从3组受试者分离的外周血单个核细胞进行体外细胞毒性试验，以检测反应性代谢产物的参与情况：正常对照受试者、耐受氯氮平治疗的精神分裂症患者（对照患者）以及服用氯氮平期间发生粒细胞缺乏症的精神分裂症患者（粒细胞缺乏症患者）。在用氯氮平与大鼠肝微粒体或氯氮平与辣根过氧化物酶 - 过氧化氢（HRP - H2O2）孵育后，测定细胞活力。

结果

在微粒体孵育中，氯氮平显著增加了所有组的细胞死亡：对照受试者（8.8%±1.6%）、对照患者（7.4%±0.4%）和粒细胞缺乏症患者（9.1%±1.5%）。然而，平均值之间的差异无统计学意义。在与HRP - H2O2的类似孵育中，与正常对照受试者（7.7%±4.1%）或对照患者（6.5%±4.4%）相比，氯氮平显著增加了粒细胞缺乏症患者细胞的毒性（P <.05）（22%±4.6%）。

结论

这些结果表明，两种生成系统都将氯氮平代谢为有毒产物。一些产物可能在氯氮平诱导的粒细胞缺乏症中起作用。具有诊断相关性的观察结果是，HRP - H2O2在粒细胞缺乏症患者细胞中产生的毒性明显大于对照患者细胞。尽管体内药物活化的确切机制尚不清楚，但HRP - H2O2对氯氮平的生物活化可能是一种有用的体外工具，可用于在治疗开始前预测哪些患者有粒细胞缺乏症的风险。