RT Journal Article
SR Electronic
T1 Drug Concentration Asymmetry in Tissues and Plasma for Small Molecule–Related Therapeutic Modalities
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 1122
OP 1135
DO 10.1124/dmd.119.086744
VO 47
IS 10
A1 Donglu Zhang
A1 Cornelis E.C.A. Hop
A1 Gabriela Patilea-Vrana
A1 Gautham Gampa
A1 Herana Kamal Seneviratne
A1 Jashvant D. Unadkat
A1 Jane R. Kenny
A1 Karthik Nagapudi
A1 Li Di
A1 Lian Zhou
A1 Mark Zak
A1 Matthew R. Wright
A1 Namandjé N. Bumpus
A1 Richard Zang
A1 Xingrong Liu
A1 Yurong Lai
A1 S. Cyrus Khojasteh
YR 2019
UL http://dmd.aspetjournals.org/content/47/10/1122.abstract
AB The well accepted “free drug hypothesis” 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–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.