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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 IC 50  values used to classify a drug as a P-gp substrate and inhibitor, respectively.Information was collected from the literature on ER and IC 50  values with digoxin as the probe substrate using different cell lines and inhibition calculation methods. Predictive performance was evaluated by comparing [I gut ]/IC 50  ratios versus reported  in vivo  results.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 IC 50  values were often observed with the Caco-2 cells and calculations based on ER. Based on the cut-off criteria of [I gut ]/IC 50  ≥ 10, there were no significant differences in positive or negative predictive values based on either cell line or calculation method for the drugs.Within this limited dataset, differences between cell lines or IC 50  calculation methods do not seem to impact the prediction of  in vivo  P-gp inhibitor classification. 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 IC 50  values used to classify a drug as a P-gp substrate and inhibitor, respectively. Information was collected from the literature on ER and IC 50  values with digoxin as the probe substrate using different cell lines and inhibition calculation methods. Predictive performance was evaluated by comparing [I gut ]/IC 50  ratios versus reported  in vivo  results. 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 IC 50  values were often observed with the Caco-2 cells and calculations based on ER. Based on the cut-off criteria of [I gut ]/IC 50  ≥ 10, there were no significant differences in positive or negative predictive values based on either cell line or calculation method for the drugs. Within this limited dataset, differences between cell lines or IC 50  calculation methods do not seem to impact the prediction of  in vivo  P-gp inhibitor classification.

xenobiotica

Do differences in cell lines and methods used for calculation of IC 50  values influence categorisation of drugs as P-glycoprotein substrates and inhibitors?