Uetrecht J P, Zahid N, Whitfield D
Faculty of Pharmacy, University of Toronto, Canada.
J Pharmacol Exp Ther. 1994 Sep;270(3):865-72.
Vesnarinone is an important new drug that significantly decreases mortality rates in severe congestive heart failure; however, its use is associated with a relatively high incidence (approximately 1%) of agranulocytosis. The authors studied its metabolism by activated neutrophils, the target for this toxicity, and evidence pointed to a pathway that involved a reactive iminium ion. Hydrolysis of the iminium ion led to a reactive quinone imine. The same pathway was observed with a combination of myeloperoxidase/hydrogen peroxide/chloride, the major oxidizing system of neutrophils, or hypochlorous acid, which is generated by this system. Activation of the neutrophils could be achieved by phorbol ester or by influenza vaccine and there is evidence to suggest that the administration of influenza vaccine during vesnarinone therapy may increase the risk of agranulocytosis. Incubation of radiolabeled vesnarinone with activated neutrophils led to covalent binding of almost 5% of the drug to the cells. Both the iminium ion and quinone imine generated by hypochlorous acid could be trapped with glutathione. It was proposed that these reactive metabolites, generated by neutrophils or neutrophil precursors in the bone marrow, may be responsible for the vesnarinone-induced agranulocytosis. Factors such as infection or vaccination that activate neutrophils may increase the risk of agranulocytosis.
维司那定是一种重要的新药，可显著降低严重充血性心力衰竭的死亡率；然而，其使用与粒细胞缺乏症的相对高发生率（约1%）相关。作者研究了它在活化中性粒细胞（这种毒性的靶点）中的代谢情况，证据指向了一条涉及反应性亚胺离子的途径。亚胺离子的水解产生了一种反应性醌亚胺。在髓过氧化物酶/过氧化氢/氯离子（中性粒细胞的主要氧化系统）或该系统产生的次氯酸的组合作用下，也观察到了相同的途径。中性粒细胞的活化可通过佛波酯或流感疫苗实现，有证据表明在维司那定治疗期间接种流感疫苗可能会增加粒细胞缺乏症的风险。将放射性标记的维司那定与活化的中性粒细胞一起孵育，结果显示近5%的药物与细胞发生共价结合。次氯酸产生的亚胺离子和醌亚胺都可以被谷胱甘肽捕获。有人提出，这些由中性粒细胞或骨髓中的中性粒细胞前体产生的反应性代谢产物可能是维司那定诱导粒细胞缺乏症的原因。诸如感染或接种疫苗等激活中性粒细胞的因素可能会增加粒细胞缺乏症的风险。
