Giacobini E, Somani S, McIlhany M, Downen M, Hallak M
Department of Pharmacology, Southern Illinois University, School of Medicine, Springfield 62708.
Neuropharmacology. 1987 Jul;26(7B):831-6. doi: 10.1016/0028-3908(87)90059-1.
The time course of physostigmine (Phy), its metabolites and activity of cholinesterase (ChE) in plasma were studied after intravenous bolus administration of [3H]Phy (100 micrograms/kg) to beagle dogs. The maximal inhibition of ChE (78%) in plasma at 2 min correlated with the largest concentration of physostigmine (124 ng/ml). The concentration of physostigmine decreased by 88% to 16 ng/ml at 45 min when the activity of ChE was still 59% inhibited. Acetylcholinesterase activity in four regions of the brain (medulla, striatum, cerebellum and cortex) was not significantly different from controls at 70 +/- 5 min after administration of physostigmine. Concentrations of physostigmine and its metabolites determined by HPLC were not significantly different in different regions. In plasma, physostigmine was found, together with eseroline and two other metabolites M1 and M2. At 45 min, only 18% of total radioactivity was due to physostigmine and 52% was due to the major metabolite M1. On the contrary, in regions of the brain, metabolite M1 represented only 1.9-3.37% of total radioactivity at 70 +/- 5 min. Pharmacokinetic parameters, obtained in the dog, were compared to previously published data in rat and man. The elimination half-life (beta) was 30.7 min in the dog as compared to 15 min in rat and and 21.7 min in man. The Vd (ml/kg) was higher than total body water volume in all three species: dog (1832), rat (1352) and man (664), indicating sequestration of the drug in body compartments. Clearance (ml/min/kg) was found to be 41.2 in dog, which compares to 62 in rat and 22 in man.(ABSTRACT TRUNCATED AT 250 WORDS)
给比格犬静脉推注[3H]毒扁豆碱（100微克/千克）后，研究了毒扁豆碱（Phy）及其代谢产物在血浆中的时程以及胆碱酯酶（ChE）的活性。给药2分钟时，血浆中ChE的最大抑制率（78%）与毒扁豆碱的最大浓度（124纳克/毫升）相关。45分钟时，毒扁豆碱浓度下降88%至16纳克/毫升，此时ChE活性仍被抑制59%。给药后70±5分钟，脑的四个区域（延髓、纹状体、小脑和皮质）的乙酰胆碱酯酶活性与对照组无显著差异。通过高效液相色谱法测定，毒扁豆碱及其代谢产物在不同区域的浓度无显著差异。在血浆中，发现了毒扁豆碱、依色林以及另外两种代谢产物M1和M2。45分钟时，总放射性中仅18%归因于毒扁豆碱，52%归因于主要代谢产物M1。相反，在脑区，70±5分钟时代谢产物M1仅占总放射性的1.9 - 3.37%。将在犬身上获得的药代动力学参数与先前发表的大鼠和人的数据进行了比较。犬的消除半衰期（β）为30.7分钟，大鼠为15分钟，人为21.7分钟。三种物种的分布容积（Vd，毫升/千克）均高于总体液量：犬（1832）、大鼠（1352）和人（664），表明药物在体内各隔室中被隔离。犬的清除率（毫升/分钟/千克）为41.2，大鼠为62，人为22。（摘要截短至250字）
