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首页> 外文期刊>Pharmacogenetics >The O-demethylation of the antidementia drug galanthamine is catalysed by cytochrome P450 2D6.
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The O-demethylation of the antidementia drug galanthamine is catalysed by cytochrome P450 2D6.

机译：抗痴呆药物加兰他敏的O-脱甲基由细胞色素P450 2D6催化。

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摘要

Galanthamine proved effective in symptomatic treatment of senile dementia of Alzheimer's type. The aim of this study was to elucidate the metabolism of galanthamine. Two novel metabolites of galanthamine have been isolated from the urine of eight young men after single doses of 10-15 mg. Some 19.8% of the doses were excreted as O-demethylgalanthamine glucuronide, 5% as N-demethylgalanthamine, 25.1% as galanthamine, and 0.8% as epigalanthamine. After coadministration of quinidine hydrogen sulfate, which inhibits cytochrome P450 2D6 (CYP2D6) selectively, O-demethylgalanthamine glucuronide was highly diminished in urine. In vitro, human liver microsomes metabolized galanthamine to O-demethylgalanthamine with Vmax 5.2 nmol/mg protein/h and Km 187 microM. Ki of quinidine to inhibit O-demethylation was 28 nM. To inhibit cholinesterases, O-demethylgalanthamine was 10-fold more selective for acetylcholinesterase (AChE) versus butyrylcholinesterase (BuChE) than galanthamine. After glucuronidation, O-demethylgalanthamine failed to inhibit AChE and BuChE. N-Demethylgalanthamine inhibited cholinesterases less potently than galanthamine.
机译：加兰他敏被证明可有效治疗阿尔茨海默氏型老年性痴呆。这项研究的目的是阐明加兰他敏的代谢。单剂10-15 mg后，已从八名年轻人的尿液中分离出两种新的加兰他敏代谢产物。约19.8％的剂量以O-去甲基加兰他敏葡糖醛酸排泄，5％以N-去甲基加兰他敏，25.1％作为加兰他敏和0.8％作为表黄甘胺排泄。选择性地抑制细胞色素P450 2D6（CYP2D6）的硫酸奎尼丁共同给药后，尿中的O-脱甲基加兰他敏葡糖苷酸含量大大降低。在体外，人肝微粒体以Vmax 5.2 nmol / mg蛋白质/ h和Km 187 microM将加兰他敏代谢为O-脱甲基加兰他敏。奎尼丁抑制O-去甲基化的Ki为28 nM。为了抑制胆碱酯酶，与去甲胆碱酯酶（BuChE）相比，O-脱甲基加兰他敏对乙酰胆碱酯酶（AChE）的选择性是对加兰他敏的十倍。葡萄糖醛酸化后，O-去甲基加兰他敏不能抑制AChE和BuChE。 N-去甲基加兰他敏对胆碱酯酶的抑制作用比加兰他敏强。

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