On the relationship between inhibition and receptor occupancy by nondepolarizing neuromuscular blocking drugs.

Q1 Mathematics
Hikaru Hoshino, Eiko Furutani
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引用次数: 1

Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

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非去极化神经肌肉阻断药物抑制与受体占用的关系。
背景:非去极化神经肌肉阻断药物(NDNBs)在临床上用于全身麻醉时产生肌肉松弛。为了更好地了解NDNBs的临床特性,我们进行了比较体外药理学研究。在这些研究中,受体结合模型已被有效地用于描述获得的实验数据,该模型依赖于抑制作用,即NDNB的作用与药物的受体占用成正比的假设。然而,在文献中还没有研究在什么条件下上述假设可以成立,也没有研究在体内仍然成立。本研究的目的是探讨NDNB的体内抑制作用与受体占用之间的关系,并对如何利用体外实验结果来讨论NDNB的体内特性提出建议。方法:采用常微分方程模型模拟乙酰胆碱(ACh)激活受体和NDNB抑制受体的生理过程。在该模型中,抑制程度通过由于NDNB的存在而未被ACh激活的受体的分数量来量化。通过绘制作为受体占用函数的激活受体的分数量来可视化结果。结果:反映体内条件的数值研究表明,抑制程度与受体占用率不成正比,即抑制程度与受体占用率之间存在非线性关系。然而,在乙酰胆碱浓度较高的情况下,反映了体外实验的典型情况,抑制作用与受体占用之间的关系变为线性关系,表明受体结合模型的有效性。此外,还发现非线性的程度取决于nndbs对受体两个结合位点的选择性。结论:虽然受体结合模型可以有效地通过体外实验估计NDNB的亲和力,但这些模型并不能直接描述NDNB的体内特性,因为抑制与受体占用之间的非线性导致了NDNB的浓度-效应关系的调节。
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来源期刊
Theoretical Biology and Medical Modelling
Theoretical Biology and Medical Modelling MATHEMATICAL & COMPUTATIONAL BIOLOGY-
自引率
0.00%
发文量
0
审稿时长
6-12 weeks
期刊介绍: Theoretical Biology and Medical Modelling is an open access peer-reviewed journal adopting a broad definition of "biology" and focusing on theoretical ideas and models associated with developments in biology and medicine. Mathematicians, biologists and clinicians of various specialisms, philosophers and historians of science are all contributing to the emergence of novel concepts in an age of systems biology, bioinformatics and computer modelling. This is the field in which Theoretical Biology and Medical Modelling operates. We welcome submissions that are technically sound and offering either improved understanding in biology and medicine or progress in theory or method.
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