Strolin Benedetti M, Cocchiara G, Colombo M, Dostert P
Research and Development, Erbamont Group, Farmitalia Carlo Erba, Milan, Italy.
J Neural Transm Suppl. 1990;32:351-6. doi: 10.1007/978-3-7091-9113-2_48.
Milacemide, a secondary amine derivative, was previously demonstrated to be a substrate of MAO-B and to be insensitive to the action of copper-dependent amine oxidases. In the present study, it was investigated whether the FAD-dependent secondary amine metabolizing enzyme polyamine oxidase (PAO), could participate in the metabolism of milacemide. For this purpose, the urinary metabolic pattern of oral 14C-milacemide was determined in rats with and without pretreatment with the irreversible PAO inhibitor MDL 72527 and, for comparison, after inhibition of MAO-B by l-deprenyl. While l-deprenyl was shown to significantly decrease the urinary excretion of glycinamide and of an unknown metabolite (UK1), pretreatment with MDL 72527 did not modify the elimination of milacemide as glycinamide but produced a decrease in UK1 equal to that induced by l-deprenyl. The percent of the dose of milacemide eliminated as unchanged drug was slightly but significantly increased after PAO inhibition, though considerably less than after l-deprenyl. These data suggest that milacemide might be a substrate of PAO. If confirmed, this result would constitute the first example of the involvement of the FAD-dependent PAO in drug metabolism.
米拉美胺是一种仲胺衍生物，先前已证明它是单胺氧化酶B（MAO - B）的底物，且对铜依赖性胺氧化酶的作用不敏感。在本研究中，研究了黄素腺嘌呤二核苷酸（FAD）依赖性仲胺代谢酶多胺氧化酶（PAO）是否参与米拉美胺的代谢。为此，在给予不可逆PAO抑制剂MDL 72527预处理和未预处理的大鼠中，测定口服14C - 米拉美胺后的尿液代谢模式，并且为了进行比较，在给予l - 司来吉兰抑制MAO - B后进行测定。虽然l - 司来吉兰显著降低了甘氨酰胺和一种未知代谢物（UK1）的尿排泄量，但用MDL 72527预处理并未改变米拉美胺以甘氨酰胺形式的消除，但使UK1的减少量与l - 司来吉兰诱导的减少量相当。在抑制PAO后，以未改变药物形式消除的米拉美胺剂量百分比略有但显著增加，尽管远低于l - 司来吉兰处理后的增加量。这些数据表明米拉美胺可能是PAO的底物。如果得到证实，这一结果将构成FAD依赖性PAO参与药物代谢的首个实例。
