Drug Concentration Asymmetry in Tissues and Plasma for Small Molecule-Related Therapeutic Modalities

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 th...

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Bibliographic Details
Published in:Drug metabolism and disposition 2019-10, Vol.47 (10), p.1122-1135
Main Authors: Zhang, Donglu, Hop, Cornelis E C A, Patilea-Vrana, Gabriela, Gampa, Gautham, Seneviratne, Herana Kamal, Unadkat, Jashvant D, Kenny, Jane R, Nagapudi, Karthik, Di, Li, Zhou, Lian, Zak, Mark, Wright, Matthew R, Bumpus, Namandjé N, Zang, Richard, Liu, Xingrong, Lai, Yurong, Khojasteh, S Cyrus
Format: Article
Language:English
Subjects:
Antibodies
Asymmetry
Binders
Biotransformation
Chemical compounds
Drug delivery
Drug delivery systems
Drug development
Drugs
Efflux
Extrusion
Forecasting
Inhalation
Minireview
Nanoparticles
Optimization
Pharmacodynamics
Pharmacology
Plasma
Prodrugs
Respiration
Steady state
Therapeutic applications
Tissues
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Summary: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 , 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., > or
ISSN:0090-9556
1521-009X
DOI:10.1124/dmd.119.086744