Frimat B, Gressier B, Odou P, Brunet C, Dine T, Luycky M, Cazin M, Cazin J C
Laboratoire de Pharmacologie, Pharmacocinetique et Pharmacie Clinique, Faculté des Sciences Pharmaceutiques et Biologiques, Lille, France.
Fundam Clin Pharmacol. 1997;11(3):267-74. doi: 10.1111/j.1472-8206.1997.tb00195.x.
The use of clozapine, an unique antipsychotic drug, raises the real problem of drug-induced polymorphonuclear neutrophil cytotoxicity. Clozapine prescription has been restricted due to a 1-2% incidence of drug-induced agranulocytosis. The exact mechanism of this adverse effect is not yet known. The myeloperoxidase-hydrogen peroxide system could play a key role in the initiation of agranulocytosis. Therefore, we have investigated the clozapine effects on hydrogen peroxide and hypochlorous acid, evaluated the peroxidase-mediated metabolism of clozapine by mass spectrometry analysis because myeloperoxidase uses hydrogen peroxide and chloride producing hypochlorous acid in its chlorination cycle, and thus could oxidise clozapine in its peroxidation cycle. First, evidence for inhibition of hypochlorous acid production and scavenging of hydrogen peroxide by clozapine were demonstrated in vitro, in different cell-free and cellular systems. Results are consistent with an inhibition of the myeloperoxidase chlorination cycle when clozapine is oxidised in the peroxidation cycle. Secondly, ion-spray mass spectrometry analysis allowed us to confirm clozapine oxidation by the myeloperoxidase system. Actually, clozapine N-oxide with a m/z at 343 was formed. It could be the final step of the metabolisation of clozapine via two successive univalent oxidations mediated by peroxidase. We suggest that generation of a free cation radical, CLZ(o+), was the initial step. CLZ(o+) is a very reactive species and may play an important role in the onset of agranulocytosis either by direct toxicity or via an immunological mechanism. However, this assumption does not exclude the possible role of other metabolic ways involving, in particular, N-desmethylclozapine.
使用氯氮平这种独特的抗精神病药物会引发药物诱导的多形核中性粒细胞细胞毒性这一实际问题。由于药物诱导的粒细胞缺乏症发生率为1 - 2%，氯氮平的处方已受到限制。这种不良反应的确切机制尚不清楚。髓过氧化物酶 - 过氧化氢系统可能在粒细胞缺乏症的引发中起关键作用。因此，我们研究了氯氮平对过氧化氢和次氯酸的影响，通过质谱分析评估了髓过氧化物酶介导的氯氮平代谢，因为髓过氧化物酶在其氯化循环中利用过氧化氢和氯离子生成次氯酸，从而可能在其过氧化循环中氧化氯氮平。首先，在不同的无细胞和细胞系统中体外证明了氯氮平抑制次氯酸生成和清除过氧化氢的证据。当氯氮平在过氧化循环中被氧化时，结果与髓过氧化物酶氯化循环的抑制一致。其次，离子喷雾质谱分析使我们能够确认髓过氧化物酶系统对氯氮平的氧化。实际上，形成了质荷比为343的氯氮平N - 氧化物。它可能是氯氮平通过过氧化物酶介导的两个连续单价氧化进行代谢的最后一步。我们认为生成游离阳离子自由基CLZ(o +)是第一步。CLZ(o +)是一种非常活泼的物质，可能通过直接毒性或免疫机制在粒细胞缺乏症的发病中起重要作用。然而，这一假设并不排除其他代谢途径的可能作用，特别是涉及N - 去甲基氯氮平的代谢途径。
