Wiciński Michał, Węclewicz Mateusz M, Miętkiewicz Mateusz, Malinowski Bartosz, Grześk Elżbieta, Klonowska Joanna
WICIŃSKI, WĘCLEWICZ, MIĘTKIEWICZ, MALINOWSKI, and GRZEŚK: Department of Pharmacology and Therapeutics, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University, Bydgoszcz, Poland KLONOWSKA: College of Engineering and Health, Warsaw, Poland.
J Psychiatr Pract. 2017 Mar;23(2):114-120. doi: 10.1097/PRA.0000000000000223.
Clozapine is a second-generation antipsychotic which has proven efficacy in treating the symptoms of schizophrenia. Although clozapine therapy is associated with a number of adverse drug reactions, it is frequently used. One of the most common adverse drug reactions is gastroesophageal reflux disease which is an indication for treatment with proton pump inhibitors (PPIs). Coadministration of clozapine and PPIs increases the risk of hematological adverse drug reactions, including neutropenia and agranulocytosis. The mechanism in idiosyncratic agranulocytosis is not dose related and involves either a direct toxic or an immune-allergic effect. It is suspected that the clozapine metabolites nitrenium ion and N-desmethylclozapine may cause apoptosis or impair growth of granulocytes. Formation of N-desmethylclozapine is correlated with activity of the cytochrome P450 enzymes 1A2 and 3A4 (CYP1A2 and CYP3A4). Nitrenium ion is produced by the flavin-containing monooxygenase system of leukocytes. A drug interaction between clozapine and a PPI is a consequence of the induction of common metabolic pathways either by the PPI or clozapine. Findings to date suggest that indirect induction of flavin-containing monooxygenase by omeprazole through the aryl hydrocarbon receptor increases the expression of the enzyme mRNA and in the long term may cause the increase in activity. Moreover, induction of CYP1A2, especially by omeprazole and lansoprazole, may increase the serum concentration of N-desmethylclozapine, which can accumulate in lymphocytes and may achieve toxic levels. Another hypothesis that may explain hematological adverse drug reactions is competitive inhibition of CYP2C19, which may contribute to increased serum concentrations of toxic metabolites.
氯氮平是一种第二代抗精神病药物，已被证明对治疗精神分裂症症状有效。尽管氯氮平治疗会引发多种药物不良反应，但它仍被广泛使用。最常见的药物不良反应之一是胃食管反流病，这是使用质子泵抑制剂（PPI）进行治疗的指征。氯氮平和PPI联合使用会增加血液学药物不良反应的风险，包括中性粒细胞减少和粒细胞缺乏症。特发性粒细胞缺乏症的机制与剂量无关，涉及直接毒性或免疫过敏效应。据推测，氯氮平代谢产物氮烯鎓离子和N-去甲基氯氮平可能导致粒细胞凋亡或抑制其生长。N-去甲基氯氮平的形成与细胞色素P450酶1A2和3A4（CYP1A2和CYP3A4）的活性相关。氮烯鎓离子由白细胞含黄素单加氧酶系统产生。氯氮平和PPI之间的药物相互作用是PPI或氯氮平诱导共同代谢途径的结果。迄今为止的研究结果表明，奥美拉唑通过芳烃受体间接诱导含黄素单加氧酶会增加该酶mRNA的表达，长期来看可能导致活性增加。此外，尤其是奥美拉唑和兰索拉唑对CYP1A2的诱导可能会增加N-去甲基氯氮平的血清浓度，其可在淋巴细胞中蓄积并可能达到中毒水平。另一种可能解释血液学药物不良反应的假说是对CYP2C19的竞争性抑制，这可能导致有毒代谢产物的血清浓度升高。
