Avdeef A
pION INC, Woburn, MA 01801, USA.
Curr Top Med Chem. 2001 Sep;1(4):277-351. doi: 10.2174/1568026013395100.
About 30% of drug candidate molecules are rejected due to pharmacokinetic-related failures. When poor pharmaceutical properties are discovered in development, the costs of bringing a potent but poorly absorbable molecule to a product stage by "formulation" can become very high. Fast and reliable in vitro prediction strategies are needed to filter out problematic molecules at the earliest stages of discovery. This review will consider recent developments in physicochemical profiling used to identify candidate molecules with physical properties related to good oral absorption. Poor solubility and poor permeability account for many PK failures. FDA's Biopharmaceutics Classification System (BCS) is an attempt to rationalize the critical components related to oral absorption. The core idea in the BCS is an in vitro transport model, centrally embracing permeability and solubility, with qualifications related to pH and dissolution. The objective of the BCS is to predict in vivo performance of drug products from in vitro measurements of permeability and solubility. In principle, the framework of the BCS could serve the interests of the earliest stages of discovery research. The BCS can be rationalized by considering Fick's first law, applied to membranes. When molecules are introduced on one side of a lipid membrane barrier (e.g., epithelial cell wall) and no such molecules are on the other side, passive diffusion will drive the molecules across the membrane. When certain simplifying assumptions are made, the flux equation in Fick's law reduces simply to a product of permeability and solubility. Many other measurable properties are closely related to permeability and solubility. Permeability (Pe) is a kinetic parameter related to lipophilicity (as indicated by the partition and distribution coefficients, log P and log D). Retention (R) of lipophilic molecules by the membrane (which is related to lipophilicity and may predict PK volumes of distribution) influences the characterization of permeability. Furthermore, strong drug interactions with serum proteins can influence permeability. The unstirred water layer on both sides of the membrane barrier can impose limits on permeability. Solubility (S) is a thermodynamic parameter, and is closely related to dissolution, a kinetic parameter. The unstirred water layer on the surfaces of suspended solids imposes limits on dissolution. Bile acids effect both solubility and dissolution, by a micellization effect. For ionizable molecules, pH plays a crucial role. The charge state that a molecule exhibits at a particular pH is characterized by the ionization constant (pKa) of the molecule. Buffers effect pH gradients in the unstirred water layers, which can dramatically affect both permeability and dissolution of ionizable molecules. In this review, we will focus on the emerging instrumental methods for the measurement of the physicochemical parameters Pe, S, pKa, R, log P, and log D (and their pH-profiles). These physicochemical profiles can be valuable tools for the medicinal chemists, aiding in the prediction of in vivo oral absorption.
约30%的候选药物分子因药代动力学相关的失败而被淘汰。在研发过程中发现药物性质不佳时，通过“制剂”将一个活性高但吸收性差的分子推进到产品阶段的成本可能会非常高。需要快速可靠的体外预测策略，以便在发现的最早阶段筛选出有问题的分子。本综述将探讨物理化学剖析方面的最新进展，这些进展用于识别具有与良好口服吸收相关物理性质的候选分子。溶解度差和渗透性差是许多药代动力学失败的原因。美国食品药品监督管理局（FDA）的生物药剂学分类系统（BCS）试图使与口服吸收相关的关键因素合理化。BCS的核心思想是一个体外转运模型，主要包括渗透性和溶解度，并对pH值和溶出度有相关限定。BCS的目标是根据渗透性和溶解度的体外测量结果预测药品的体内性能。原则上，BCS的框架可以服务于发现研究的最早阶段。通过考虑应用于膜的菲克第一定律，可以使BCS合理化。当分子被引入脂质膜屏障的一侧（例如上皮细胞壁）而另一侧没有此类分子时，被动扩散将驱使分子穿过膜。当做出某些简化假设时，菲克定律中的通量方程简化为渗透性和溶解度的乘积。许多其他可测量的性质与渗透性和溶解度密切相关。渗透性（Pe）是一个与亲脂性相关的动力学参数（如由分配系数和分布系数log P和log D所示）。膜对亲脂性分子的保留（R）（与亲脂性相关，可能预测药代动力学分布容积）影响渗透性的表征。此外，药物与血清蛋白的强烈相互作用会影响渗透性。膜屏障两侧的静止水层会对渗透性施加限制。溶解度（S）是一个热力学参数，与溶出度密切相关，溶出度是一个动力学参数。悬浮固体表面的静止水层对溶出度施加限制。胆汁酸通过胶束化作用影响溶解度和溶出度。对于可离子化分子，pH值起着至关重要的作用。分子在特定pH值下呈现的电荷状态由分子的电离常数（pKa）表征。缓冲液会影响静止水层中的pH梯度，这会显著影响可离子化分子的渗透性和溶出度。在本综述中，我们将重点关注用于测量物理化学参数Pe、S、pKa、R、log P和log D（及其pH分布图）的新兴仪器方法。这些物理化学分布图对于药物化学家来说可能是有价值的工具，有助于预测体内口服吸收情况。
