De Haes Ann, Proost Johannes H, De Baets Mark H, Stassen Maurice H W, Houwertjes Martin C, Wierda J Mark K H
Research Group for Experimental Anesthesiology and Clinical Pharmacology, University Hospital Groningen, Groningen, The Netherlands.
Anesthesiology. 2003 Jan;98(1):133-42. doi: 10.1097/00000542-200301000-00022.
In myasthenic patients, the sensitivity for nondepolarizing relaxants is increased and the time course of effect is prolonged due to a reduced number of functional acetylcholine receptors at the neuromuscular junction. The authors investigated both the performance of the link model proposed by Sheiner and a pharmacodynamic-pharmacokinetic model taking into account the number of unbound acetylcholine receptors in myasthenic pigs.
After obtaining the approval of the Animal Experiments Committee of their institution, the authors studied eight myasthenic pigs and eight control pigs. Myasthenia gravis was induced by injecting Torpedo acetylcholine receptors in weeks 1 and 4. On the day of the experiments, the pigs were anesthetized and intubated, and the appropriate muscles and nerves were prepared for the measurements. Rocuronium was administered by infusion to reach 90% twitch height block. Arterial blood was sampled during onset and offset of effect, and the plasma concentration of rocuronium was measured with high-performance liquid chromatography. Plasma concentration-time effect data were analyzed using two different pharmacokinetic-pharmacodynamic models, the link model according to Sheiner and a pharmacokinetic-pharmacodynamic model taking into account the unbound receptor concentration. Muscles were removed after the experiment for laboratory analysis of the acetylcholine receptor concentration.
All eight pigs of the myasthenic group developed clinical signs of myasthenia gravis (muscle weakness) and showed increased sensitivity toward rocuronium. Pharmacokinetic modeling revealed no significant differences between myasthenic and control pigs. In pharmacokinetic-pharmacodynamic analysis, visual inspection as well as the Akaike Information Criterion (3,605 3,769) and the residual SD (3.2 3.6%) revealed a better fit for the unbound receptor model in myasthenic animals compared to the Sheiner model. Pharmacokinetic-pharmacodynamic analysis with the unbound receptor model demonstrated a decreased EC50 of 0.27 micro m (ranging from 0.17 to 0.59 micro m) compared to 2.71 micro m (ranging from 2.42 to 4.43 micro m) in control animals. The results of the Sheiner pharmacokinetic-pharmacodynamic analysis were in the same range. Both the laboratory analysis and pharmacokinetic-pharmacodynamic modeling showed a decrease in receptor concentration of more than 75%.
Both the Sheiner model and the unbound receptor model may be used to fit plasma concentration-effect data of rocuronium in pigs. The unbound receptor concentration model, however, can explain the observed differences in the time course of effect, based on receptor concentration.
在重症肌无力患者中，由于神经肌肉接头处功能性乙酰胆碱受体数量减少，对非去极化肌松药的敏感性增加，作用时间延长。作者研究了Sheiner提出的连接模型以及考虑重症肌无力猪体内未结合乙酰胆碱受体数量的药代动力学-药效学模型的性能。
在获得所在机构动物实验委员会的批准后，作者研究了8只重症肌无力猪和8只对照猪。在第1周和第4周注射电鳐乙酰胆碱受体诱导重症肌无力。在实验当天，将猪麻醉并插管，准备好合适的肌肉和神经用于测量。通过输注罗库溴铵达到90%的颤搐高度阻滞。在效应起效和消退期间采集动脉血，用高效液相色谱法测量罗库溴铵的血浆浓度。使用两种不同的药代动力学-药效学模型分析血浆浓度-效应数据，即根据Sheiner的连接模型和考虑未结合受体浓度的药代动力学-药效学模型。实验结束后取出肌肉用于乙酰胆碱受体浓度的实验室分析。
重症肌无力组的所有8只猪均出现重症肌无力的临床体征（肌无力），对罗库溴铵的敏感性增加。药代动力学建模显示重症肌无力猪和对照猪之间无显著差异。在药代动力学-药效学分析中，目视检查以及赤池信息准则（3605对3769）和残余标准差（3.2%对3.6%）显示，与Sheiner模型相比，未结合受体模型对重症肌无力动物的拟合更好。使用未结合受体模型进行药代动力学-药效学分析显示，与对照动物的2.71μm（范围为2.42至4.43μm）相比，半数有效浓度（EC50）降低至0.27μm（范围为0.17至0.59μm）。Sheiner药代动力学-药效学分析的结果在相同范围内。实验室分析和药代动力学-药效学建模均显示受体浓度降低超过75%。
Sheiner模型和未结合受体模型均可用于拟合猪体内罗库溴铵的血浆浓度-效应数据。然而，未结合受体浓度模型可以根据受体浓度解释观察到的效应时间过程差异。
