Brain levels and acetylcholinesterase inhibition with galantamine and donepezil in rats, mice, and rabbits
Brain levels and acetylcholinesterase inhibition with galantamine and donepezil in rats, mice, and rabbits
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DOI：
10.1016/j.brainres.2004.11.042
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发表时间：
2005-02-08
期刊：
影响因子：
2.9
通讯作者：
Sachak, S
中科院分区：
文献类型：
--
作者：
Geerts, H;Guillaumat, PO;Sachak, S
加兰他敏是一种相当弱的乙酰胆碱酯酶（AChE）抑制剂，目前已批准用于阿尔茨海默病的对症治疗，可能对烟碱乙酰胆碱受体（nAChR）具有额外的变构增效作用。早期的体外生化试验数据表明，多奈哌齐在抑制乙酰胆碱酯酶方面的效力是加兰他敏的40至500倍。在本研究中，测定了多奈哌齐和加兰他敏在大鼠、小鼠和兔皮下给药后的脑水平和AChE抑制的Ki值。加兰他敏从脑中的清除通常比多奈哌齐更快，并且在兔中比大鼠和小鼠更快。加兰他敏和多奈哌齐的脑-血浆比分别在兔中为1.2 - 1.5，小鼠中为3.3 - 5.2，大鼠中为6.6 - 13。1.5 - 5 mg/kg的加兰他敏剂量适合于在记录的最佳变构增强配体剂量-反应内达到脑水平。加兰他敏和多奈哌齐抑制脑AChE的Ki值在大鼠中分别为7.1和2.3 μ g/g，在小鼠中分别为8.3和0.65 μ g/g，在兔中分别为19.1和1.3 μ g/g。数据还表明，对于类似程度的脑AChE抑制，需要比多奈哌齐高3-15倍的加兰他敏剂量。(C)2004 Elsevier B. V.保留所有权利。
Galantamine is a rather weak acetylcholinesterase (AChE) inhibitor, currently approved for the symptomatic treatment of Alzheimer's disease, with possible additional allosteric potentiating effects at the nicotinic ACh receptor (nAChR). Earlier data from in vitro biochemical tests suggest that donepezil is 40- to 500-fold more potent than galantamine in inhibiting AChE. In this study, both brain levels and K-i values for AChE inhibition for donepezil and galantamine in rat, mouse, and rabbit after subcutaneous application were determined. Clearance of galantamine from the brain is in general faster that donepezil and is faster in rabbits compared to rats and mice. The brain-to-plasma ratio for galantamine and donepezil, respectively, ranges from 1.2 to 1.5 in the rabbit, 3.3 to 5.2 in the mouse, and 6.6 to 13 in the rat. Galantamine doses between 1.5 and 5 mg/kg are appropriate to reach brain levels within the documented optimal allosteric potentiating ligand dose-response. K-i values of brain AChE inhibition for galantamine and donepezil, respectively, are 7.1 and 2.3 mug/g in rats, 8.3 and 0.65 mug/g for mice, and 19.1 and 1.3 mug/g in rabbits. The data also suggest that for a similar degree of brain AChE inhibition, 3-15 times higher galantamine than donepezil doses are needed. (C) 2004 Elsevier B.V. All rights reserved.