Even though significant efforts have been spent in recent years to understand and define the determinants of in vivo potency and clearance, important pieces of information are still lacking. By introducing target turnover into the reasoning, we open up to further the understanding of central factors important to the optimization of translational dose–concentration–response predictions. We describe (i) new (open model) expressions of the in vivo potency and efficacy parameters, which embody target turnover, binding, and complex kinetics, also capturing full, partial, and inverse agonism and antagonism; (ii) a detailed examination of open models to show what potency and efficacy parameters have in common and how they differ; and (iii) a comprehensive literature review showing that target turnover rate varies with age, species, tissue/subregion, treatment, disease state, hormonal and nutritional state, and day–night cycle. The new open model expression, which integrates system and drug properties, shows the following. Fractional turnover rates rather than the absolute target or ligand–target complex expression determine necessary drug exposure via in vivo potency. Absolute ligand–target expression determines the need of a drug, based on the transduction ρ and in vivo efficacy parameters. The free enzyme concentration determines clearance and maximum metabolic rate. The fractional turnover rate determines time to equilibrium between substrate, free enzyme, and complex.The properties of substrate, target, and the complex demonstrate nonsaturable metabolic behavior at equilibrium. Nonlinear processes, previously referred to as capacity- and time-dependent kinetics, may occasionally have been disequilibria. Finally, the open model may pinpoint why some subjects differ in their demand of drug.

中文翻译：

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打开，收听，营业额！靶标生物学影响体内效力、功效和清除率

尽管近年来已经付出了巨大的努力来理解和定义体内效力和清除率的决定因素，但仍然缺乏重要的信息。通过将目标转换引入推理，我们可以进一步理解对转化剂量-浓度-反应预测的优化很重要的核心因素。我们描述了 (i) 体内效能和功效参数的新（开放模型）表达式，其中体现了目标转换、结合和复杂的动力学，还捕获了完全、部分和反向激动和拮抗作用；(ii) 对开放模型的详细检查，以显示效力和功效参数的共同点和不同点；(iii) 全面的文献综述表明目标周转率随年龄、物种、组织/次区域而变化，治疗、疾病状态、荷尔蒙和营养状态以及昼夜循环。整合了系统和药物特性的新开放模型表达式如下所示。分数周转率而不是绝对靶标或配体-靶标复合物表达通过体内效力确定必要的药物暴露。基于转导，绝对配体-靶标表达决定了药物的需求ρ和体内功效参数。游离酶浓度决定清除率和最大代谢率。周转率分数决定了底物、游离酶和复合物之间达到平衡的时间。底物、靶标和复合物的特性表明平衡时的非饱和代谢行为。非线性过程，以前称为容量和时间依赖动力学，有时可能是不平衡的。最后，开放模型可以查明为什么有些受试者对药物的需求不同。