AbstractThe distribution, metabolism, and pharmacokinetics of physostigmine (Phy) and the time course of butyrylcholinesterase (BuChE) in plasma and cholinesterase (ChE) activity in brain and muscle and their relationship to Phy concentration were described after oral administration of3H‐Phy (650 μg kg−1) to rats. Physostigmine concentration vs time data was analyzed by nonlinear computer fitting program using one‐compartment model. The absorption rate constant (ka) and elimination rate constant (ke) were found to be 0·1 ± 0·07 min−1and 0·036 ± 0·024 min−1, respectively.Cpmaxandtmaxwere 3·3 ng ml−1and 16 min. The clearance (Cl) was found to be 80·9 ml min−1kg−1. Half‐life of Phy in brain, muscle, and liver were 33·4min, 22·5, and 28 min, respectively. The bioavailability (F) was calculated to be 0·02 and the extraction ratio was found to be 0·98 indicating the ‘first pass’ effect. Butyrylcholinesterase activity in plasma was 76 per cent at 15 min and this activity did not change significantly up to 120 min. However, Phy concentration in plasma was very low; 2·89 ng ml−1at 15 min and declined to 0.71 ng ml−1at 90 min. Physostigmine concentration in brain peaked at 22 min to 2·85 ± 1·09 ng g−1and declined to 0·33 ± 0·11 ng g−1at 60 min. Cholinesterase activity in brain was 96 per cent, 82 per cent and 89 per cent at 10, 45, and 120 min, respectively. Physostigmine concentration in muscle was very low and the ChE activity in the muscle was 66·4 per cent of control at 45 min. The time course of Phy metabolism indicated that at 5 min most of the RA in the tissues was due to metabolites accounting for 94·6 per cent in plasma, 90 per cent in liver, 79·8 per cent in brain and 86·3 per cent in muscle. M1appeared to be the major metabolite followed by eseroline. The results showed extremely low concentrations of Phy (200 times less in plasma and 350 times less in brain) after oral administration compared to our previous
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机译：摘要 大鼠口服3H-Phy（650 μg kg−1）后，描述了大鼠口服3H-Phy（650 μg kg−1）后，毒扁豆碱（Phy）的分布、代谢和药代动力学以及丁酰胆碱酯酶（BuChE）在脑和肌肉血浆和胆碱酯酶（ChE）活性中的时程及其与Phy浓度的关系。使用单室模型通过非线性计算机拟合程序分析毒扁豆碱浓度与时间数据的关系。吸收速率常数（ka）和消除速率常数（ke）分别为0·1±0·07 min−1和0·036 ±0·024 min−1。Cpmaxandtmax分别为3·3 ng ml−1和16 min。发现间隙（Cl）为80·9 ml min-1kg-1。Phy在脑、肌肉和肝脏中的半衰期分别为33·4min、22·5和28 min。计算生物利用度（F）为0·02，提取比为0·98，表明“首过”效应。15分钟时，血浆中的丁酰胆碱酯酶活性为76%，该活性在120分钟内没有显着变化。然而，血浆中的Phy浓度非常低;2·89 ng ml-1在15分钟，在90分钟时降至0.71 ng ml-1。脑中毒扁豆碱浓度在22 min时达到峰值，达到2·85±1·09 ng g−1，在60 min时降至0·33±0·11 ng g−1。在10、45和120分钟时，大脑中的胆碱酯酶活性分别为96%、82%和89%。肌肉中的毒扁豆碱浓度非常低，45 min时肌肉中的ChE活性为对照组的66.4%。Phy代谢时间进程表明，在5 min时，组织中RA大部分由代谢物引起，其中代谢物在血浆中占94·6%，在肝脏中占90%，在脑中占79·8%，在肌肉中占86·3%。M1似乎是主要代谢物，其次是依血清素。结果显示，与我们之前相比，口服给药后 Phy 的浓度极低（血浆中的浓度降低 200 倍，大脑中的浓度降低 350 倍）
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