Evolving approaches on measurements and applications of intracellular free drug concentration and Kp_uu in drug discovery

Abstract

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.

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