Potency is a central parameter in pharmacological and biochemical sciences, as well as in drug discovery and development endeavors. It is however typically defined in terms only of ligand to target binding affinity also in in vivo experimentation, thus in a manner analogous to in in vitro studies. As in vivo potency is in fact a conglomerate of events involving ligand, target, and target-ligand complex processes, overlooking some of the fundamental differences between in vivo and in vitro may result in serious mispredictions of in vivo efficacious dose and exposure. The analysis presented in this paper compares potency measures derived from three model situations. Model A represents the closed in vitro system, defining target binding of a ligand when total target and ligand concentrations remain static and constant. Model B describes an open in vivo system with ligand input and clearance (Cl_(L)), adding in parallel to the turnover (k_syn, k_deg) of the target. Model C further adds to the open in vivo system in Model B also the elimination of the target-ligand complex (k_e(RL)) via a first-order process. We formulate corresponding equations of the equilibrium (steady-state) relationships between target and ligand, and complex and ligand for each of the three model systems and graphically illustrate the resulting simulations. These equilibrium relationships demonstrate the relative impact of target and target-ligand complex turnover, and are easier to interpret than the more commonly used ligand-, target- and complex concentration-time courses. A new potency expression, labeled L₅₀, is then derived. L₅₀ is the ligand concentration at half-maximal target and complex concentrations and is an amalgamation of target turnover, target-ligand binding and complex elimination parameters estimated from concentration-time data. L₅₀ is then compared to the dissociation constant K_d (target-ligand binding affinity), the conventional Black & Leff potency estimate EC₅₀, and the derived Michaelis-Menten parameter K_m (target-ligand binding and complex removal) across a set of literature data. It is evident from a comparison between parameters derived from in vitro vs. in vivo experiments that L₅₀ can be either numerically greater or smaller than the K_d (or K_m) parameter, primarily depending on the ratio of k_deg-to-k_e(RL). Contrasting the limit values of target R and target-ligand complex RL for ligand concentrations approaching infinity demonstrates that the outcome of the three models differs to a great extent. Based on the analysis we propose that a better understanding of in vivo pharmacological potency requires simultaneous assessment of the impact of its underlying determinants in the open system setting. We propose that L₅₀ will be a useful parameter guiding predictions of the effective concentration range, for translational purposes, and assessment of in vivo target occupancy/suppression by ligand, since it also encompasses target turnover – in turn also subject to influence by pathophysiology and drug treatment. Different compounds may have similar binding affinity for a target in vitro (same K_d), but vastly different potencies in vivo. L₅₀ points to what parameters need to be taken into account, and particularly that closed-system (in vitro) parameters should not be first choice when ranking compounds in vivo (open system).

在药理学和生化科学以及药物发现和开发工作中，效价是关键参数。然而，通常在体内实验中也仅根据配体对靶标的结合亲和力来定义，因此以类似于体外研究的方式来定义。由于体内效力实际上是涉及配体，靶标和靶标配体复杂过程的综合事件，因此忽略体内和体外之间的一些基本差异可能会导致严重的体内错误预测有效剂量和暴露。本文提供的分析比较了从三种模型情况得出的效价测度。模型A代表封闭的体外系统，当总靶标和配体浓度保持静态和恒定时，定义了配体的靶标结合。模型B描述了一个开放的体内系统，该系统具有配体输入和清除率（Cl _（L）），并与靶标的周转率（k _syn，k _deg）平行添加。模型C进一步增加了模型B的开放体内系统，还消除了目标配体复合物（k _e（RL））通过一阶过程。我们针对三个模型系统中的每一个，为目标和配体之间以及配体和配体之间的平衡（稳态）关系制定了相应的方程式，并以图形方式说明了所得的模拟结果。这些平衡关系证明了靶标和靶标配体复杂转换的相对影响，并且比更常用的配体，靶标和复杂浓度-时间过程更容易解​​释。然后，得出一个新的效能表达式，标记为L ₅₀。L ₅₀是在最大目标浓度和复合物浓度的一半时的配体浓度，是目标浓度，目标-配体结合和根据浓度-时间数据估算的复合物消除参数的合并。然后将L ₅₀与解离常数K _d（目标-配体结合亲和力），常规Black＆Leff效能估计值EC ₅₀和一组推导的Michaelis-Menten参数K _m（目标-配体结合和复合物去除）进行比较。文学数据。从体外与体外衍生的参数之间的比较可以明显看出。体内实验表明L ₅₀可以是数值上比更大或更小ķ _d（或ķ_米）参数，主要取决于比率ķ_度-到- ķ _È（RL）。将目标R和目标配体络合物RL的极限值与接近无限大的配体进行对比，表明这三个模型的结果差异很大。基于分析，我们建议对体内药理学效力有一个更好的了解，需要同时评估其潜在决定因素在开放系统环境中的影响。我们建议L ₅₀这将是一个有用的参数，可指导有效浓度范围的预测（用于翻译目的）以及评估配体对体内靶标的占有/抑制，因为它还包括靶标转换率-进而还受到病理生理学和药物治疗的影响。不同化合物可以具有针对目标相似的结合亲和力在体外（相同ķ _d），但大大不同的效力的体内。L ₅₀指出需要考虑哪些参数，特别是在对体内化合物（开放系统）进行排名时，封闭系统（体外）参数不应该是首选。