Nondepolarizing neuromuscular blocking drugs (NDNBs) are clinically used to produce muscle relaxation during general anesthesia. To better understand clinical properties of NDNBs, comparative in vitro pharmacologic studies have been performed. In these studies, a receptor binding model, which relies on the assumption that the inhibition, i.e., the effect of an NDNB, is proportional to the receptor occupancy by the drug, has been effectively used to describe obtained experimental data. However, it has not been studied in literature under which conditions the above assumption can be justified nor the assumption still holds in vivo. The purpose of this study is to explore the in vivo relationship between the inhibition and the receptor occupancy by an NDNB and to draw implications on how in vitro experimental results can be used to discuss the in vivo properties of NDNBs. An ordinary differential equation model is employed to simulate physiologic processes of the activation of receptors by acetylcholine (ACh) as well as inhibition by an NDNB. With this model, the degree of inhibition is quantified by the fractional amount of receptors that are not activated by ACh due to the presence of an NDNB. The results are visualized by plotting the fractional amounts of the activated receptors as a function of the receptor occupancy. Numerical investigations reflecting in vivo conditions show that the degree of inhibition is not proportional to the receptor occupancy, i.e., there is a nonlinear relationship between the inhibition and the receptor occupancy. However, under a setting of high concentration of ACh reflecting a typical situation of in vitro experiments, the relationship between the inhibition and the receptor occupancy becomes linear, suggesting the validity of the receptor binding model. Also, it is found that the extent of nonlinearity depends on the selectivity of NDNBs for the two binding sites of the receptors. While the receptor binding model may be effective for estimating affinity of an NDNB through in vitro experiments, these models do not directly describe in vivo properties of NDNBs, because the nonlinearity between the inhibition and the receptor occupancy causes the modulation of the resultant concentration-effect relationships of NDNBs.

中文翻译：

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非去极化神经肌肉阻滞药物抑制作用与受体占有率的关系

非去极化神经肌肉阻滞药物 (NDNB) 临床上用于在全身麻醉期间产生肌肉松弛。为了更好地了解 NDNB 的临床特性，已经进行了比较体外药理学研究。在这些研究中，依赖于抑制作用（即 NDNB 的作用）与药物对受体的占有率成正比的假设的受体结合模型已被有效地用于描述获得的实验数据。然而，在文献中还没有研究在何种条件下上述假设是合理的，或者该假设在体内仍然成立。本研究的目的是探索 NDNB 的抑制作用与受体占有率之间的体内关系，并对如何使用体外实验结果来讨论 NDNB 的体内特性提出启示。采用常微分方程模型来模拟乙酰胆碱 (ACh) 激活受体以及 NDNB 抑制的生理过程。在该模型中，抑制程度通过因 NDNB 的存在而未被 ACh 激活的受体的分数来量化。结果通过绘制作为受体占有率函数的活化受体的分数来可视化。反映体内条件的数值研究表明，抑制程度与受体占有率不成正比，即，抑制与受体占有率之间存在非线性关系。然而，在反映体外实验典型情况的高浓度ACh设置下，抑制与受体占有率之间的关系变为线性，表明受体结合模型的有效性。此外，还发现非线性程度取决于 NDNB 对受体的两个结合位点的选择性。虽然受体结合模型可能通过体外实验有效估计 NDNB 的亲和力，但这些模型并没有直接描述 NDNB 的体内特性，因为抑制和受体占据之间的非线性导致对合成浓度效应的调节NDNB 的关系。