Clozapine toxicity: Role of pharmacogenetic variation in CYP enzymes and bioactivation mechanisms in patient neutrophils

精神分裂症等精神疾病的治疗涉及给患者服用强效药物组合。然而，有些人对常用的抗精神病药物没有反应，他们的病情只能通过一种叫做氯氮平的独特药物来改善。氯氮平的主要问题是它对血细胞、心脏和其他器官的毒性。所有接受氯氮平的人都必须密切监测，特别是在开始治疗后的头3-4个月。一些新药被认为是氯氮平的安全版本，但这些都是无效的。氯氮平是唯一一种对其他治疗精神分裂症药物无效的人有效的药物。因此，氯氮平的毒性需要停药，这是一个毁灭性的结果，因为没有其他治疗方法可用。氯氮平的另一个重要问题是，它从体内排出的速度被许多其他同时使用的药物减慢了。氯氮平的问题发生在一些人身上，但不是所有人。这表明，患者的基因组成和他们对药物和环境因素的暴露决定了毒性的发生率。目前的项目着眼于氯氮平如何从体内排出，以及它如何转化为损害细胞的有毒产物。这些过程将被检查，重点是个体患者之间的差异，并将测试保护细胞免受有毒衍生物损害的策略。相应的研究将在接受氯氮平治疗精神病的患者中进行。我们将能够比较实验和临床结果，以确定那些似乎有风险的患者。这将在毒性作用发生之前成为可能，并将帮助我们确定应该谨慎使用该药物的受试者。我们也可以设计出一些策略，将毒性的发生率降到最低。

The treatment of mental disorders such as schizophrenia involves the administration of potent drug combinations to patients. Some individuals, however, do not respond to commonly-used antipsychotic drugs and their condition only improves with a unique drug called clozapine. The major problem with clozapine is its toxicity toward blood cells, heart and other organs. All people who receive clozapine must be monitored closely, especially in the first 3-4 months after starting therapy. Several new drugs have been suggested to be safer versions of clozapine but these are all ineffective. Clozapine is the only agent that is effective in people who do not respond to the other drugs used to treat schizophrenia. Thus, clozapine toxicity, which necessitates discontinuation of the drug, is a devastating outcome because there is no alternative treatment that is available. Another significant problem with clozapine is that its rate of removal from the body is slowed down by many other drugs that are used concurrently. The problems with clozapine occur in some but not all individuals. This suggests that the patient's genetic makeup and their exposure to drugs and environmental agents determine the incidence of toxicity. The present project looks at how clozapine is removed from the body and how it is converted into a toxic product that damages cells. These processes will be examined, with emphasis on differences between individual patients, and strategies to protect cells from damage from the toxic derivative will be tested. Corresponding studies will be done in patients who are receiving clozapine as treatment for psychoses. We will be able to compare experimental and clinical findings in order to identify those patients who appear to be at risk. This will be possible before the toxic effects occur and will help us to identify subjects in whom the drug should only be used with great care. We may also devise strategies that will minimise the incidence of toxicity.