Orthogonal chromatographic descriptors for modelling Caco-2 drug permeability

Area of Science:

• Pharmacokinetics and Drug Metabolism
• Computational Chemistry
• Analytical Chemistry

Background:

• Caco-2 permeability assays are standard for predicting oral drug absorption but are time-consuming and resource-intensive.
• Chromatographic descriptors offer a potential high-throughput alternative for early-stage drug absorption screening.
• Developing robust quantitative structure-activity relationship (QSAR) models requires careful selection of orthogonal chromatographic systems.

Purpose of the Study:

• To evaluate the utility of chromatographic descriptors as surrogates for Caco-2 permeability in drug absorption screening.
• To develop and validate a QSAR model for predicting drug absorption using chromatographic data.
• To identify optimal chromatographic systems and physicochemical parameters for accurate prediction.

Main Methods:

• Measured retentions on 17 orthogonal Reversed-Phase Liquid Chromatography (RPLC) systems and one Immobilized Artificial Membrane (IAM) system.
• Utilized literature data for retentions on a Micellar Liquid Chromatography (MLC) system.
• Selected dissimilar chromatographic systems and employed retention factors as descriptors in Stepwise Multiple Linear Regression (SMLR) for QSAR modeling.
• Incorporated lipophilicity (Moriguchi n-octanol/water partition coefficient) and molecular volume into the final QSAR model.

Main Results:

• A QSAR model was developed using retention data from only two selected chromatographic systems, demonstrating good descriptive and acceptable predictive performance.
• The final, high-quality model integrated two chromatographic systems with lipophilicity and molecular volume.
• The combined model achieved superior predictive accuracy for drug absorption compared to models based solely on chromatographic data.

Conclusions:

• Chromatographic descriptors, particularly when combined with physicochemical parameters, can effectively predict drug absorption.
• A minimal set of orthogonal chromatographic systems, coupled with molecular descriptors, can replace traditional Caco-2 permeability assays for initial drug screening.
• This approach offers a more efficient and cost-effective strategy for early-stage drug development and pharmacokinetic profiling.