THE RELATIONSHIP BETWEEN RECEPTOR-EFFECTOR UNIT HETEROGENEITY AND THE SHAPE OF THE CONCENTRATION-EFFECT PROFILE - PHARMACODYNAMIC IMPLICATIONS
THE RELATIONSHIP BETWEEN RECEPTOR-EFFECTOR UNIT HETEROGENEITY AND THE SHAPE OF THE CONCENTRATION-EFFECT PROFILE - PHARMACODYNAMIC IMPLICATIONS
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DOI：
10.1007/bf02353789
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发表时间：
1994-12-01
期刊：
影响因子：
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通讯作者：
GOLDBERG, A
中科院分区：
文献类型：
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作者：
HOFFMAN, A;GOLDBERG, A
表观浓度-效应关系是许多效应单元（如单个细胞或通道）的整体，这些效应单元并不总是表现出一致的刺激-效应关系。这一概念得到了证实的异质性受体效应群体，包括激素分泌细胞，激素刺激的反应，第二信使的活动模式，刺激诱发的突触电流，和单离子通道的许多观察。药物浓度与药理学反应幅度之间的关系通常由S形E（max）模型描述，该模型源自Hill方程。该模型中的S形因子（N）被假定为没有生理内涵的纯数学参数。这项工作表明，N的数值（经验测量）是两个因素的产物。(i)效应子亚基的异质性程度，即，在药物刺激下独立地贡献其药理学作用并且不与其他亚基相互作用的元素组分（其范围可以从单个受体到整个组织），以及（ii）N* 的值-亚基浓度-效应关系的形状因子。当N*>5时，出现这种方法的特殊情况，这是开-关情况。这里N由子单元值的分布（密度方程）确定。在效应器的微观参数的异质性的情况下。在子单元中，表观N将总是具有比N* 更低的值。根据这一理论，可以得出结论，没有知识的微观参数的分布没有机制的解释可以从表观N值推导出来。如果将来可以通过理论或实验方法确定N*，则可以计算出N* 与N之间的分布函数。鉴于先进的研究技术正在取得进展，这一理论的相关性增加，这可能使我们能够确定在单个效应单元水平上的浓度-效应关系。
The apparent concentration-effect relationship is the ensemble of many effector units (such as individual cells or channels) that do not always exhibit a uniform stimu]us-effect relationship. This concept is substantiated by many observations of heterogeneity in receptor-effector populations including hormone secreting cells, response to hormonal stimuli, activity patter of second messengers, stimulus-evoked synaptic currents, and single ion channels. The relationship between drug concentration and magnitude of pharmacologic response is commonly described by the sigmoidal E(max), model which was derived from the Hill equation. The sigmoidicity factor (N) in this model is assumed to be a pure mathematical parameter without physiological connotations. This work demonstrates that the numerical value of N (measured empirically) is the product of two factors. (i) tire degree of heterogeneity of the effector subunits, i.e., the elemental component that upon drug stimulus contributes its pharmacological effect independently and does not interact with other subunits (it could range from a single receptor up to a whole tissue), and (ii) value of N*-the shape factor of the subunits' concentration-effect relationship. A special case of this approach occurs when N*>5, which is an on-off case. Here N is determined by the distribution (density equation) of the subunit values. In case of heterogeneity of the microparameters of the effector. subunits the apparent N will always have a lower value than N*. According to this theory it can be concluded that without knowledge of the distribution of the microparameters no mechanistic interpretation can be deduced from the apparent N value. If in the future N* can be determined bg theoretical or experimental methods, the distribution function relating N* to N can be calculated. The relevance of this theory is increased in view of the progress being made in advanced research techniques which may enable us to determine the concentration-effect relationship at the level of the individual effector unit.