Rational Use of Plasma Protein and Tissue Binding Data in Drug Design
- 6 August 2014
- journal article
- review article
- Published by American Chemical Society (ACS) in Journal of Medicinal Chemistry
- Vol. 57 (20), 8238-8248
- https://doi.org/10.1021/jm5007935
Abstract
It is a commonly accepted assumption that only unbound drug molecules are available to interact with their targets. Therefore, one of the objectives in drug design is to optimize the compound structure to increase in vivo unbound drug concentration. In this review, theoretical analyses and experimental observations are presented to illustrate that low plasma protein binding does not necessarily lead to high in vivo unbound plasma concentration. Similarly, low brain tissue binding does not lead to high in vivo unbound brain tissue concentration. Instead, low intrinsic clearance leads to high in vivo unbound plasma concentration, and low efflux transport activity at the blood–brain barrier leads to high unbound brain concentration. Plasma protein and brain tissue binding are very important parameters in understanding pharmacokinetics, pharmacodynamics, and toxicities of drugs, but these parameters should not be targeted for optimization in drug design.Keywords
This publication has 60 references indexed in Scilit:
- The effect of plasma protein binding on in vivo efficacy: misconceptions in drug discoveryNature Reviews Drug Discovery, 2010
- Significance of Protein Binding in Pharmacokinetics and PharmacodynamicsJournal of Pharmaceutical Sciences, 2010
- CSF as a Surrogate for Assessing CNS Exposure: An Industrial PerspectiveCurrent Drug Metabolism, 2008
- On The Rate and Extent of Drug Delivery to the BrainPharmaceutical Research, 2007
- Misuse of the Well-Stirred Model of Hepatic Drug Clearance: Fig. 1.Published by American Society for Pharmacology & Experimental Therapeutics (ASPET) ,2007
- The importance of plasma protein binding in drug discoveryExpert Opinion on Drug Discovery, 2007
- Plasma Protein Binding Affinity and Its Relationship to Molecular Structure: An In-silico AnalysisJournal of Medicinal Chemistry, 2006
- Fast Gradient HPLC Method to Determine Compounds Binding to Human Serum Albumin. Relationships with Octanol/Water and Immobilized Artificial Membrane LipophilicityJournal of Pharmaceutical Sciences, 2003
- Development and validation of a 96-well equilibrium dialysis apparatus for measuring plasma protein bindingJournal of Pharmaceutical Sciences, 2003
- Development of a High Throughput Equilibrium Dialysis MethodJournal of Pharmaceutical Sciences, 2001