简介:无细胞药物浓度(Cu,细胞)和未结合分配系数(Kpuu)是发展药代动力学和药效学关系的两个重要参数,预测药物-药物相互作用潜力和估计治疗指数。覆盖面积:铜的测量方法,cell,Kpuu,讨论了分配系数(Kp)和细胞未结合分数(fuc)。综述了几种fuc方法的优点和局限性。这里强调的应用是弥合生物化学和基于细胞的测定之间的效力差距,体外肝细胞测定法预测体内肝脏对血浆的Kpuu,Kpuu在使用扩展清除方程预测酶和转运体介导的机制的肝清除中的作用,和控制组织Kpuu的结构属性。专家意见:Cu,cell和Kpuu在药物发现中的应用越来越多。用于测量这些性质的方法继续发展,以便实现更高的精度/准确度并在亚细胞水平上获得更详细的信息。该领域的未来方向包括开发体外和计算机模型来预测组织Kpuu,直接测量亚细胞器中的游离药物浓度,并进一步研究控制细胞和组织Kpuu的关键因素。需要重大创新来推进这个综合体,而是极具影响力和令人兴奋的科学领域。
Introduction: Intracellular-free drug concentration (Cu,cell) and unbound partition coefficient (Kpuu) are two important parameters to develop pharmacokinetic and pharmacodynamic relationships, predict drug-drug interaction potentials and estimate therapeutic indices.Area covered: Methods on measurements of Cu,cell, Kpuu, partition coefficient (Kp) and fraction unbound of cells (fuc) are discussed. Advantages and limitations of several fuc methods are reviewed. Applications highlighted here are bridging the potency gaps between biochemical and cell-based assays, in vitro hepatocyte assay to predict in vivo liver-to-plasma Kpuu, the role of Kpuu in prediction of hepatic clearance for enzyme- and transporter-mediated mechanisms using extended clearance equation, and structural attributes governing tissue Kpuu.Expert opinion: Cu,cell and Kpuu are of growing applications in drug discovery. Methods for measurements of these properties continue to evolve in order to achieve higher precision/accuracy and obtain more detailed information at the subcellular levels. Future directions of the field include the development of in vitro and in silico models to predict tissue Kpuu, direct measurement of free drug concentration in subcellular organelles, and further investigations into the critical elements governing cell and tissue Kpuu. Significant innovation is needed to advance this complex, but highly impactful and exciting area of science.