Transporter Phenotyping and Inhibition

Permeability-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) are drug efflux transporter proteins situated in apical membranes of several organs including liver, kidney, testes, placenta, brain, and gastrointestinal tract. Both transporters can impact drug kinetics as well as safety and/or efficacy since they restrict the distribution of their substrates into these tissues and may also contribute to eliminating substrates via renal and biliary excretion, and intestinal secretion.

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P-gp and BCRP Phenotyping

Our in vitro drug transporter assays are designed to assess the P-gp and BCRP substrate properties of (radiolabeled) drug candidates. The concentration and time-dependent bi-directional permeability and derived efflux ratio of the test compound are determined in Caco-2 monolayer cells. If polarized transport is observed indicating that it is a transporter substrate, the percentage inhibition of its efflux ratio is investigated under linear transport rate conditions in the absence and presence of prototypical P-gp or BCRP inhibitors.

P-gp and BCRP Inhibition

In order to evaluate the potential of a drug candidate to inhibit P-gp and BCRP, the bi-directional permeability and resulting efflux ratio of prototypical P‑gp and BCRP substrates are determined in Caco-2 monolayer cells in the absence and presence of the test compound at different concentrations. If applicable, its concentration required for 50% inhibition (IC50) of the maximum transport mediated by P-gp or BCRP is calculated.

Evaluation of possible interactions between the drug candidate and other efflux and uptake transporters as required by regulatory agencies are available upon request.

RELATED TOPICS: DDI package

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