Do differences in cell lines and methods used for calculation of IC₅₀ values influence categorisation of drugs as P-glycoprotein substrates and inhibitors?

Abstract

1. In vitro bidirectional assays are employed to determine whether a drug is a substrate and/or inhibitor of P-glycoprotein (P-gp) transport. Differences between cell lines and calculation methods can lead to variations in the determination of efflux ratios (ER) and IC₅₀ values used to classify a drug as a P-gp substrate and inhibitor, respectively.

2. Information was collected from the literature on ER and IC₅₀ values with digoxin as the probe substrate using different cell lines and inhibition calculation methods. Predictive performance was evaluated by comparing [I_gut]/IC₅₀ ratios versus reported in vivo results.

3. For known P-gp substrates, 50% of the drugs had their highest ER value in MDCK-MDR1 cells while 81% had their lowest ER value in Caco-2 cells. For 30 drugs with inhibition data, lower mean IC₅₀ values were often observed with the Caco-2 cells and calculations based on ER. Based on the cut-off criteria of [I_gut]/IC₅₀ ≥ 10, there were no significant differences in positive or negative predictive values based on either cell line or calculation method for the drugs.

4. Within this limited dataset, differences between cell lines or IC₅₀ calculation methods do not seem to impact the prediction of in vivo P-gp inhibitor classification.

Keywords:

• P-glycoprotein
• efflux
• IC₅₀ values
• cell lines
• predictive performance

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No potential conflict of interest was reported by the author(s).

Data availability statement

The authors confirm that all the literature references for the data supporting the findings of this study are available within the supplementary materials.

Additional information

Funding

The author(s) reported there is no funding associated with the work featured in this article.