Efflux transporter inhibition, cell permeation

Permeability of probe substrates across human MDR1/Pgp and BCRP overexpressing MDCKII cell lines to both directions is measured in the presence and absence of the test compound to evaluate the inhibition of MDR1/Pgp and BCRP mediated transport. Test compound analysis can be included in the experiment.
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Test concentrations: 4

Time points: 0, 60 min

Replicates: 2

Positive controls

UPLC/MS/MS analysis

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Bi-directional apparent permeability

Inhibition towards efflux transporters as % inhibition and IC50 values, if applicable

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Background

A family of ATP binding cassette (ABC) transporters is an important group of membrane transporters involved in drug absorption, distribution and elimination. Regulatory authorities recommend investigating the potential roles of ABC superfamily members ABCB1 (MDR1, P-glycoprotein), and ABCG2 (BCRP) for transporter-mediated drug-drug interactions (DDI), by evaluating whether the new drug candidate is a substrate (potential DDI victim) or an inhibitor (potential DDI perpetrator) towards drug transporters. Additionally, evaluation of inhibition towards bile salt export pump (BSEP, ABCB11) is recommended due to safety concerns associated with inhibition of this transporter. A family of solute carriers (SLC) is an important group of membrane transporters involved in drug absorption, distribution and elimination. Regulatory authorities recommend investigating the potential roles of SLC superfamily members OATP1B1, OATP1B3, OAT1, OAT3, OCT2, MATE1 and MATE2 for transporter-mediated drug-drug interactions (DDI), by evaluating whether the new drug candidate is a substrate (potential DDI victim) or an inhibitor (potential DDI perpetrator) towards drug transporters. In addition, it is also worthwhile considering investigation of OCT1, whenever in vitro and in vivo findings suggest its involvement in DDI to be anticipated.

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