Comparison of effective and membrane permeability of drugs in development of in silico model

Authors

• KR Yu
• P Shah
• X Xu

Abstract

Cell membrane permeability is one of the key factors that affect the oral absorption and bioavailability of a drug molecule in human body. Parallel artificial membrane permeability assay (PAMPA) is commonly used to evaluate the drug permeability across an artificial cell membrane, which resembles to that of a gastrointestinal tract or blood-brain barrier. The assay is a time and cost-efficient technique that can yield effective permeability values on a high throughput scale. In addition, its tolerance to wide pH range allows the compounds to be tested under different pH conditions; the data can then be used to calculate the membrane permeability under different biological conditions. Compared to effective permeability, which is affected by aqueous boundary layer (ABL), the membrane permeability measures true permeability across a given membrane. The goal of this study is to develop a useful mathematical model that is highly predictive and can serve as a useful tool for medicinal chemists to design and synthesize drug compounds with optimal drug characteristics. For this study, we determined the effective permeability (pH 7.4) and membrane permeability (pH 5.0 and 7.4) for a set of about 100 compounds using PAMPA. These results will be used to build quantitative structure-permeability relationship (QSPR) models. Predicted permeability values for reference compounds generated from these two respective models will then be compared to permeability values obtained from Caco-2 assays in literature. We plan to supplement the better model with additional compounds to use as a tool for reliable permeability predictions in the future.

Scientific Focus Area: Research Support Services

This page was last updated on Friday, March 26, 2021