GALANTHAMINE - PHARMACOKINETICS, TISSUE DISTRIBUTION AND CHOLINESTERASE INHIBITION IN BRAIN OF MICE
GALANTHAMINE - PHARMACOKINETICS, TISSUE DISTRIBUTION AND CHOLINESTERASE INHIBITION IN BRAIN OF MICE
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DOI：
10.1016/0028-3908(91)90005-v
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发表时间：
1991-05-01
影响因子：
4.7
通讯作者：
KEWITZ, H
中科院分区：
文献类型：
--
作者：
BICKEL, U;THOMSEN, T;KEWITZ, H
小鼠静脉注射加兰他敏4、6、8 mg/kg后，用反相高效液相色谱-荧光检测法测定血浆和组织提取物中的加兰他明。在4 mg/kg剂量后，血药浓度呈双指数下降，终末半衰期为43.3min。分布体积(V(Ss))为2.17 L/kg，与包括人在内的其他物种的分布体积相似。对不活跃的非对映异构体--表没食子胺的代谢非常有限。加兰他明在组织中迅速积累，在肾脏(是血浆的10倍)和肝脏(是血浆的5倍)中最明显。在脑中，蓄积与其他实质器官(隔膜、肺)相似，达2.10倍。红细胞的浓度是血浆的1.34倍。加兰他明在组织中的积累，除了肝脏和肾脏，可以解释为被动分布根据pH值的差异，在细胞内和细胞外的隔室。脑血流量(1.05mlmin-1g-1)范围内的清除量表明，加兰他明从血液到脑组织的提取是完全的。在终末消除阶段，加兰他明在脑组织中的浓度-时间曲线与血浆中的浓度-时间曲线平行。对同一脑组织标本的乙酰胆碱酯酶(AChE)抑制实验表明，脑匀浆(1：4w/v磷酸盐缓冲液，4 mg/kg，注射后5min)对乙酰胆碱酯酶(AChE)的最大表观抑制率为43%。对乙酰胆碱酯酶抑制的测定和从体外浓度-反应曲线(IC503.9×10(-6)M)和加兰他明的测定浓度获得的估计值在所研究的时间段(给药后1-180min)显示出良好的一致性。讨论了根据测得的AChE血药浓度和体外浓度-抑制曲线估算AChE体内抑制作用的可行性。
Galanthamine was determined in plasma and tissue extracts of mice, after the application of 4, 6 and 8 mg/kg (i.v.), by reverse phase HPLC, with fluorescence detection. A biexponential decline of concentrations in plasma, with a terminal half-life of 43.3 min, was observed after the dose of 4 mg/kg. The volume of distribution (V(ss)) of 2.17 l/kg was similar to that found in other species, including man. Metabolism to the inactive diastereomer, epigalanthamine, was very limited. There was a rapid accumulation of galanthamine in tissues, which was most pronounced in the kidney (10-fold compared to plasma) and liver (5-fold). In brain, accumulation was similar to other parenchymatous organs (diaphragm, lung) and amounted to 2.10-fold. Red blood cells showed a concentration 1.34-fold greater than plasma. The accumulation of galanthamine in tissue, with the exception of liver and kidney, can be explained by passive distribution according to differences in pH, between intra- and extracellular compartments. Extraction of galanthamine from blood to brain tissue was complete, indicated by a clearance in the range of cerebral blood flow (1.05 ml min-1 g-1). The concentration-time course of galanthamine in brain tissue was parallel to that in plasma during the terminal elimination phase. Measurement of inhibition of acetylcholinesterase (AChE) in the same samples from brain revealed a maximum apparent inhibition of 43% in the homogenate of brain (1:4 w/v in phosphate buffer, 4 mg/kg, 5 min after injection). Measured inhibition of AChE and estimated values, taken from the in vitro concentration-response curve (IC50 3.9 x 10(-6) M) and from measured concentrations of galanthamine, displayed a good concordance over the period examined (1-180 min after application). The feasibility of estimating inhibition of AChE in vivo from measured concentrations in plasma and in vitro concentration-inhibition curves is discussed.