Efflux transporter inhibition, vesicular uptake

Efflux transporter inhibition of the test compound is evaluated by measuring the vesicular uptake of a probe substrate into inside-out membrane vesicles expressing a single human ABC transporter (MDR1/Pgp, BCRP, BSEP, MRP2 and/or MRP3) in the absence and presence of the test compound at selected concentrations with and without ATP. Transporter inhibition is observed as reduced level of vesicular uptake of the probe substrate in the presence of ATP.
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Test concentrations: 6

Time points: 1

Replicates: 2

Positive controls

UPLC/MS/MS analysis

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Transporter mediated uptake rate of probe substrates in presence and absence of the study compound

Inhibition towards efflux transporters as % inhibition and as IC50 values when 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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