Studies on the in vitro conversion of haloperidol to a potentially neurotoxic pyridinium metabolite.
Studies on the in vitro conversion of haloperidol to a potentially neurotoxic pyridinium metabolite.
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DOI：
10.1021/tx00019a017
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发表时间：
1991
影响因子：
4.1
通讯作者：
Babu Subramanyam;T. Woolf;N. Castagnoli
中科院分区：
文献类型：
--
作者：
Babu Subramanyam;T. Woolf;N. Castagnoli
有证据表明，部分氧化的哌啶衍生物，如帕金森诱导剂1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）在单胺氧化酶B （MAO-B）催化的反应中转化为神经毒性的吡啶代谢物，从而在药物治疗大鼠的尿液中鉴定了氟哌啶醇衍生的吡啶代谢物。目前的体外研究检查了控制这种整体四电子氧化的代谢途径。虽然氟哌啶醇及其1,2,3,6-四氢吡啶脱水产物不是纯化牛肝脏MAO-B的底物，但这两种化合物都可以通过大鼠肝微粒体制剂生物转化为吡啶产物。对NADPH的依赖和SKF-525A的抑制表明，一种或多种肝细胞色素P-450同工酶可能催化这种转化。检测可能的代谢中间体的尝试没有成功。然而，化学模型研究表明，预期的中间氨基烯醇和二氢吡啶可能太不稳定而无法分离。考虑到该途径在氟哌啶醇诱导的中枢神经系统功能障碍方面的可能意义。
Evidence that partially oxidized piperidine derivatives such as the Parkinsonian inducing agent 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) are biotransformed in a reaction catalyzed by monoamine oxidase B (MAO-B) to neurotoxic pyridinium metabolites led to studies resulting in the identification of the haloperidol-derived pyridinium metabolite in the urine of drug-treated rats. The present in vitro studies examine the metabolic pathway governing this overall four-electron oxidation. Although haloperidol and its 1,2,3,6-tetrahydropyridine dehydration product were not substrates for purified bovine liver MAO-B, both compounds were biotransformed to the pyridinium product by rat liver microsomal preparations. The dependence on NADPH and the inhibition by SKF-525A argue that one or more liver cytochrome P-450 isozymes may catalyze this transformation. Attempts to detect possible metabolic intermediates were not successful. Chemical model studies, however, suggest that the expected intermediary amino enol and dihydropyridinium species may be too unstable to isolate. The possible significance of this pathway with respect to haloperidol-induced central nervous system dysfunction is considered.