Abstract
It is a commonly accepted assumption that only unbound drug molecules are available to interact with their targets. In order to achieve high unbound plasma drug concentration, it seems obvious to design compounds with low plasma protein binding. Similarly to achieve high unbound tissue concentration, we apparently need compounds with low tissue binding. Our theoretical analysis and experimental data demonstrate that unbound plasma concentration is not determined by plasma protein binding but by hepatic intrinsic clearance after oral dose, and unbound tissue concentration is not determined by tissue binding but determined by unbound plasma concentration and transport properties at the blood-tissue barrier. Reduction of plasma and tissue protein binding for a compound will increase the unbound concentration in vitro but may not increase its unbound plasma or tissue concentration in vivo after oral administration. We conclude that plasma protein and tissue binding are essential parameters to understand pharmacokinetics and pharmacodynamics but they should not be optimized independently in drug discovery. Instead we should focus on reducing clearance and efflux at the blood-tissue barrier to increase in vivo plasma and tissue unbound concentration.
Keywords: Clearance, drug design, free/unbound drug concentration, plasma protein binding, tissue binding
Current Topics in Medicinal Chemistry
Title: Do We Need to Optimize Plasma Protein and Tissue Binding in Drug Discovery?
Volume: 11 Issue: 4
Author(s): Xingrong Liu, Cuiping Chen and Cornelis E.C.A. Hop
Affiliation:
Keywords: Clearance, drug design, free/unbound drug concentration, plasma protein binding, tissue binding
Abstract: It is a commonly accepted assumption that only unbound drug molecules are available to interact with their targets. In order to achieve high unbound plasma drug concentration, it seems obvious to design compounds with low plasma protein binding. Similarly to achieve high unbound tissue concentration, we apparently need compounds with low tissue binding. Our theoretical analysis and experimental data demonstrate that unbound plasma concentration is not determined by plasma protein binding but by hepatic intrinsic clearance after oral dose, and unbound tissue concentration is not determined by tissue binding but determined by unbound plasma concentration and transport properties at the blood-tissue barrier. Reduction of plasma and tissue protein binding for a compound will increase the unbound concentration in vitro but may not increase its unbound plasma or tissue concentration in vivo after oral administration. We conclude that plasma protein and tissue binding are essential parameters to understand pharmacokinetics and pharmacodynamics but they should not be optimized independently in drug discovery. Instead we should focus on reducing clearance and efflux at the blood-tissue barrier to increase in vivo plasma and tissue unbound concentration.
Export Options
About this article
Cite this article as:
Liu Xingrong, Chen Cuiping and E.C.A. Hop Cornelis, Do We Need to Optimize Plasma Protein and Tissue Binding in Drug Discovery?, Current Topics in Medicinal Chemistry 2011; 11 (4) . https://dx.doi.org/10.2174/156802611794480918
DOI https://dx.doi.org/10.2174/156802611794480918 |
Print ISSN 1568-0266 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4294 |
Call for Papers in Thematic Issues
Chemistry Based on Natural Products for Therapeutic Purposes
The development of new pharmaceuticals for a wide range of medical conditions has long relied on the identification of promising natural products (NPs). There are over sixty percent of cancer, infectious illness, and CNS disease medications that include an NP pharmacophore, according to the Food and Drug Administration. Since NP ...read more
Current Trends in Drug Discovery Based on Artificial Intelligence and Computer-Aided Drug Design
Drug development discovery has faced several challenges over the years. In fact, the evolution of classical approaches to modern methods using computational methods, or Computer-Aided Drug Design (CADD), has shown promising and essential results in any drug discovery campaign. Among these methods, molecular docking is one of the most notable ...read more
Drug Discovery in the Age of Artificial Intelligence
In the age of artificial intelligence (AI), we have witnessed a significant boom in AI techniques for drug discovery. AI techniques are increasingly integrated and accelerating the drug discovery process. These developments have not only attracted the attention of academia and industry but also raised important questions regarding the selection ...read more
From Biodiversity to Chemical Diversity: Focus of Flavonoids
Flavonoids are the largest group of polyphenols, plant secondary metabolites arising from the essential aromatic amino acid phenylalanine (or more rarely from tyrosine) via the phenylpropanoid pathway. The flavan nucleus is the basic 15-carbon skeleton of flavonoids (C6-C3-C6), which consists of two phenyl rings (A and B) and a heterocyclic ...read more
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
- Announcements