Metabolism of clozapine by rat brain: the role of flavin-containing monooxygenase (FMO) and cytochrome P450 enzymes
Metabolism of clozapine by rat brain: the role of flavin-containing monooxygenase (FMO) and cytochrome P450 enzymes
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DOI：
10.1007/bf03190076
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发表时间：
2000-04-01
影响因子：
1.9
通讯作者：
Fang, J
中科院分区：
文献类型：
--
作者：
Fang, J
据报道，非典型抗精神病药物氯氮平主要代谢为N-氧化物和N-去甲基化产物。众所周知，氯氮平的靶器官大脑中含有许多药物代谢酶，这些酶可能会改变药物的局部浓度。因此，我们研究了氯氮平在大鼠脑内的代谢。氯氮平N-氧化物是大鼠脑内的主要代谢途径，我们用大鼠脑标本表征了氯氮平的N-氧化作用。K-m和V-max分别为319.6微米和28.1pmol/min/mg蛋白。硫脲(一种含黄素的单加氧酶抑制剂)可抑制氯氮平N-氧化物的形成，但不能被酮康唑、奎尼丁或呋喃茶碱所抑制。这一发现表明，FMO显著参与了氯氮平在大鼠脑内的N-氧合作用。进一步证实了这一结论，观察到氯氮平N-氧化物的形成对脑制剂的热处理很敏感，并且可以通过NADPH产生系统的存在部分地防止热退化。进一步观察到，在pH 8.5时，氯氮平的N-氧化速率远高于在pH 7.4时。综上所述，这些数据表明，N-氧合是大鼠脑催化的主要代谢途径，这一反应主要由FMO催化。由于脑FMO活性存在显著的个体差异，这些差异可能是患者对氯氮平反应的个体差异的原因之一。
The atypical antipsychotic clozapine has been reported to be metabolised mainly to its N-oxide and N-demethylated products. Brain, the target organ of clozapine, is known to contain numerous drug-metabolising enzymes which could alter the local concentrations of the drug. The metabolism of clozapine was, therefore, studied in rat brain preparations. Clozapine N-oxide was the major metabolic pathway in rat brain.We characterised the N-oxygenation of clozapine by rat brain preparations. The K-m and V-max values were found to be 3 19.6 muM and 28.1 pmol/min/mg protein, respectively. The formation of clozapine N-oxide was shown to be inhibited by thiourea (a flavin-containing monooxygenase inhibitor) but not by ketoconazole, quinidine or furafylline. This finding suggests prominent involvement of FMO in the N-oxygenafion of clozapine in rat brain. This conclusion was further confirmed by the observation that the formation of clozapine N-oxide is sensitive to heat treatment of the brain preparation and can be partially protected from thermal degeneration by the presence of an NADPH generating system. It was further observed that the rate of clozapine N-oxygenation was much higher at pH 8.5 than at pH 7.4. Taken together, the data suggest that N-oxygenation is the major metabolic pathway catalysed by rat brain and this reaction is catalysed mainly by FMO.As significant interindividual differences have been observed in brain FMO activities, these differences may contribute to the interindividual differences in patient response to clozapine.