Scientific Resources

A repository of information to support drug discovery projects in the physchem space
Bio-Mimetic Chromatography and in vivo drug distribution              

The Problem

Volume distribution and its uses

A major concern for the pharmaceutical industry is the high attrition rate (>90 per cent) of potential drug molecules failing during late stages of the drug discovery process. This may be due to lack of efficacy in the clinic, unexpected side effects or unfavourable pharmacokinetics.

There is a need for new tools to predict the in vivo distribution of discovery compounds earlier in the drug discovery process, thus reducing the investment in molecules failing unexpectedly in later, more expensive stages of the drug development. There are many in silico prediction tools for estimating pharmaco-kinetic and toxicological effects of compounds based on their chemical structures or physico-chemical properties.

The volume of distribution reveals how a drug molecule distributes between the plasma and tissue compartment, but it does not provide information on how the compound distributes between various tissues.

For drugs that are designed to go to the brain for the required pharmacological effect, we would prefer high brain tissue accumulation together with high free brain concentration. For drugs designed to cure lung diseases for example, we would prefer that the compounds partition preferentially into the lung. Different tissues contain various amounts and types of proteins and phospholipids. Therefore, we can assume that an appropriate combination of the biomimetic binding properties show good correlation with various tissue binding data.

Bio-mimetic vs Octanol/Water

Useful Presentations

Based on the Abraham solvation equation approach octanol/water log P has very similar solvation equation to phospholipid (IAM) and albumin (HSA) binding for neutral compounds. They all have very little sensitivity towards H-bond acidity of the molecules. However, the log P model fails for ionisable compounds. Lipophilicity (log D) drops for ionized compounds regardless whether the type of charge is positive or negative.  Phospholipid binding remains strong for positively charged compounds while albumin binding remains strong for negatively charged compounds.

The type of charge on the molecule at physiological pH drives a compound’s distribution between the plasma and tissues. Bio-mimetic chromatographic measurements of IAM and HSA bindings are more informative than log D. See comparison of logP/D with bio-mimetic properties.

Lipophilicity and bio-mimetic properties measured by HPLC to support drug discovery
Lipophilicity in drug discovery
Comparison of logP/D with bio-mimetic properties