Obach R Scott, Dalvie Deepak K
Department of Pharmacokinetics, Dynamics, and Drug Metabolism, Pfizer Global Research and Development, Groton Laboratories, Groton, CT 06340, USA.
Drug Metab Dispos. 2006 Aug;34(8):1310-6. doi: 10.1124/dmd.106.010173. Epub 2006 May 5.
Nomifensine is an antidepressant agent that was removed from use because of a high incidence of hemolytic anemia. It contains an N-methyl-8-aminotetrahydroisoquinoline ring which has the potential to be oxidized to quaternary dihydroisoquinolinium and isoquinolinium ions, albeit such a transformation had not been previously observed. In this report, we demonstrate the conversion of nomifensine to a dihydroisoquinolinium ion metabolite by several human enzymes. Human liver microsomes supplemented with NADPH generated the dihydroisoquinolinium ion metabolite along with other hydroxylated metabolites, whereas when supplemented with t-butyl peroxide, only the dihydroisoquinolinium ion metabolite was observed. Monoamine oxidase A, but not monoamine oxidase B, catalyzed this reaction, as well as human hemoglobin supplemented with H2O2. Human myeloperoxidase catalyzed this reaction in the presence of H2O2, and activation of the reaction was observed when incubations were conducted in the presence of acetaminophen at concentrations relevant to those measured in humans. The reaction was also observed in human whole blood. The equilibrium between the dihydroisoquinolinium ion and carbinolamine was shown to have a pK of about 11.7. The dihydroisoquinolinium ion was shown to react with cyanide and borohydride, but not glutathione. These findings suggest that the electrophilic nomifensine dihydroisoquinolinium metabolite, which can be generated by several enzymes, could be behind toxic responses to nomifensine such as hemolytic anemia and hepatotoxicity.
诺米芬辛是一种抗抑郁药，因其溶血性贫血发生率高而被停用。它含有一个N-甲基-8-氨基四氢异喹啉环，有可能被氧化为季铵二氢异喹啉离子和异喹啉离子，尽管此前尚未观察到这种转化。在本报告中，我们证明了几种人体酶可将诺米芬辛转化为二氢异喹啉离子代谢物。添加了NADPH的人肝微粒体除了产生其他羟基化代谢物外，还生成了二氢异喹啉离子代谢物，而添加叔丁基过氧化物时，仅观察到二氢异喹啉离子代谢物。单胺氧化酶A而非单胺氧化酶B催化了该反应，添加了H2O2的人血红蛋白也能催化。人髓过氧化物酶在H2O2存在下催化该反应，并且在对乙酰氨基酚存在下以与人体测量浓度相关的浓度进行孵育时观察到反应活化。在人全血中也观察到了该反应。二氢异喹啉离子与甲醇胺之间的平衡显示pK约为11.7。已证明二氢异喹啉离子可与氰化物和硼氢化物反应，但不与谷胱甘肽反应。这些发现表明，可由多种酶生成的亲电诺米芬辛二氢异喹啉代谢物可能是诺米芬辛产生溶血性贫血和肝毒性等毒性反应的原因。
