P-gp inhibition potential in cell-based models: which "calculation" method is the most accurate?

The AAPS Journal
Praveen V BalimaneSaeho Chong

Abstract

The objective was to directly compare the four different "calculation" methods of assessing P-gp inhibition potential using experimental data obtained from approximately 60 structurally diverse internal research and marketed compounds. Bidirectional studies for digoxin (probe for P-gp substrate) were performed with and without test compounds (at 10 microM). Four different calculation methods were applied to the same dataset (raw bidirectional permeability values) to obtain the "percent inhibition of P-gp" for these compounds using the different methods. Significantly different inhibition potential was obtained with the "exact" same experimental dataset depending on the calculation method used. Subsequently, entirely different conclusions regarding the "inhibition potential" of test compound was reached due to the different calculation methods. Based on the direct comparison of these methods, method no. 3 (i.e., inhibition of B to A permeability of digoxin) is recommended as the calculation method ideal during screening stages due to its high throughput amenability. The methodology is capable of rapidly screening compounds with adequate reliability for early stage drug discovery. Method no. 3 provides an abridged version of a bi...Continue Reading

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