UK Bioanalysis Immunogenicity and Biomarkers, GSK R&D, Stevenage, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, UK.
Drug Metabolism and Pharmacokinetics, GSK R&D, Stevenage, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, UK.
Pharm Res. 2022 Feb;39(2):213-222. doi: 10.1007/s11095-022-03172-7. Epub 2022 Feb 2.
The Free Drug Hypothesis is a well-established concept within the scientific lexicon pervading many areas of Drug Discovery and Development, and yet it is poorly defined by virtue of many variations appearing in the literature. Clearly, unbound drug is in dynamic equilibrium with respect to absorption, distribution, metabolism, elimination, and indeed, interaction with the desired pharmacological target. Binding interactions be they specific (e.g. high affinity) or nonspecific (e.g. lower affinity/higher capacity) are governed by the same fundamental physicochemical tenets including Hill-Langmuir Isotherms, the Law of Mass Action and Drug Receptor Theory. With this in mind, it is time to recognise a more coherent version and consider it the Free Drug Theory and a hypothesis no longer. Today, we have the experimental and modelling capabilities, pharmacological knowledge, and an improved understanding of unbound drug distribution (e.g. Kp) to raise the bar on our understanding and analysis of experimental data. The burden of proof should be to rule out mechanistic possibilities and/or experimental error before jumping to the conclusion that any observations contradict these fundamentals.
游离药物假说在药物发现和开发的许多领域都是一个既定的科学概念，但由于文献中出现了许多变体，因此该假说的定义并不明确。显然，游离药物在吸收、分布、代谢、消除以及与预期的药理靶标相互作用方面处于动态平衡。结合相互作用无论是特异性的（例如高亲和力）还是非特异性的（例如低亲和力/高容量），都受相同的基本物理化学原理支配，包括希尔朗缪尔等温线、质量作用定律和药物受体理论。考虑到这一点，现在是时候认识到一个更连贯的版本了，并将其视为游离药物理论，而不再是一个假说。如今，我们拥有实验和建模能力、药理学知识以及对游离药物分布（例如 Kp）的更深入理解，这使得我们能够提高对实验数据的理解和分析水平。在得出任何观察结果与这些基本原理相矛盾的结论之前，应该先排除可能的机制或实验误差，这才是证明的责任。
