Correlation of drug absorption with molecular surface properties

Area of Science:

• Pharmacology
• Computational Chemistry
• Drug Delivery

Background:

• Drug absorption is crucial for oral bioavailability.
• Predicting drug absorption involves understanding molecular interactions with intestinal models.
• Traditional methods like log P may not fully capture dynamic molecular properties.

Purpose of the Study:

• To investigate the correlation between dynamic molecular surface properties and drug absorption.
• To compare the predictive power of dynamic surface area versus partition coefficients for drug permeability.
• To evaluate novel in vitro models for assessing oral drug absorption.

Main Methods:

• Calculated dynamic molecular surface properties (van der Waals, water-accessible surface area) for beta-adrenoreceptor antagonists using molecular mechanics and Boltzmann distribution.
• Assessed drug permeability using Caco-2 cell monolayers and rat intestinal segments.
• Computed octanol/buffer partition coefficients (log Doct,7.4) for comparison.

Main Results:

• Excellent correlations found between dynamic polar van der Waals surface area and permeability in Caco-2 cells (r2=0.99) and rat ileum (r2=0.92).
• These correlations surpassed those of calculated log Doct,7.4 with permeability (r2=0.80 and 0.73).
• Log Doct,7.4 values failed to correctly rank permeability coefficients in the tested models.

Conclusions:

• Dynamic polar surface area is a superior predictor of oral drug absorption compared to traditional partition coefficients.
• This dynamic property offers a promising alternative for predicting drug permeability in early drug development.
• The study highlights the importance of considering molecular flexibility and dynamic properties in drug absorption modeling.