@article {Zhang1122, author = {Donglu Zhang and Cornelis E.C.A. Hop and Gabriela Patilea-Vrana and Gautham Gampa and Herana Kamal Seneviratne and Jashvant D. Unadkat and Jane R. Kenny and Karthik Nagapudi and Li Di and Lian Zhou and Mark Zak and Matthew R. Wright and Namandj{\'e} N. Bumpus and Richard Zang and Xingrong Liu and Yurong Lai and S. Cyrus Khojasteh}, title = {Drug Concentration Asymmetry in Tissues and Plasma for Small Molecule{\textendash}Related Therapeutic Modalities}, volume = {47}, number = {10}, pages = {1122--1135}, year = {2019}, doi = {10.1124/dmd.119.086744}, publisher = {American Society for Pharmacology and Experimental Therapeutics}, abstract = {The well accepted {\textquotedblleft}free drug hypothesis{\textquotedblright} for small-molecule drugs assumes that only the free (unbound) drug concentration at the therapeutic target can elicit a pharmacologic effect. Unbound (free) drug concentrations in plasma are readily measurable and are often used as surrogates for the drug concentrations at the site of pharmacologic action in pharmacokinetic-pharmacodynamic analysis and clinical dose projection in drug discovery. Furthermore, for permeable compounds at pharmacokinetic steady state, the free drug concentration in tissue is likely a close approximation of that in plasma; however, several factors can create and maintain disequilibrium between the free drug concentration in plasma and tissue, leading to free drug concentration asymmetry. These factors include drug uptake and extrusion mechanisms involving the uptake and efflux drug transporters, intracellular biotransformation of prodrugs, membrane receptor{\textendash}mediated uptake of antibody-drug conjugates, pH gradients, unique distribution properties (covalent binders, nanoparticles), and local drug delivery (e.g., inhalation). The impact of these factors on the free drug concentrations in tissues can be represented by Kp,uu, the ratio of free drug concentration between tissue and plasma at steady state. This review focuses on situations in which free drug concentrations in tissues may differ from those in plasma (e.g., Kp,uu \> or \<1) and discusses the limitations of the surrogate approach of using plasma-free drug concentration to predict free drug concentrations in tissue. This is an important consideration for novel therapeutic modalities since systemic exposure as a driver of pharmacologic effects may provide limited value in guiding compound optimization, selection, and advancement. Ultimately, a deeper understanding of the relationship between free drug concentrations in plasma and tissues is needed.}, issn = {0090-9556}, URL = {https://dmd.aspetjournals.org/content/47/10/1122}, eprint = {https://dmd.aspetjournals.org/content/47/10/1122.full.pdf}, journal = {Drug Metabolism and Disposition} }