Permeability and transporters

In vitro permeability assays for drug absorption and tissue distribution

Assessing the permeability of drug candidates across biological membranes and investigating the involvement of drug transporters is crucial for understanding oral bioavailability and tissue distribution, including the ability to cross the blood-brain barrier.

A scientist examines a cell culture flask under a microscope, focusing on cellular structures and growth patterns.

Permeability

Permeability can be assessed using Caco-2 cells (human colon carcinoma cell line) with different assays and setups, in the absence and presence of specific drug transporter inhibitors to identify active transport processes. Both unlabelled and radiolabelled test compounds can be used.

Transporter phenotyping and Inhibition

Permeability-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) are drug efflux transporters found in the apical membranes of several organs, including the liver, kidney, testes, placenta, brain and gastrointestinal tract. These transporters can impact drug kinetics, safety and efficacy by restricting the distribution of their substrates and contributing to their elimination via renal, intestinal and biliary excretion.

P-gp and BCRP phenotyping

Our in vitro drug transporter assays assess the P-gp and BCRP substrate properties of a (radiolabelled) drug candidate. We determine the concentration and time-dependent bi-directional permeability and derived efflux ratio of the test compound. If polarized transport is observed, indicating it is a transporter substrate, we investigate the percentage inhibition of its efflux ratio under linear transport rate conditions in the absence and presence of prototypical P-gp or BCRP inhibitors.

P-gp and BCRP inhibition

To investigate a drug candidate's potential to inhibit P-gp and BCRP, we determine the bi-directional permeability and resulting efflux ratio of prototypical P-gp and BCRP substrates in the absence and presence of the test compound at different concentrations. If applicable, we calculate the concentration required for 50% inhibition (IC50) of the maximum transport mediated by P-gp or BCRP. Evaluations of interactions between the drug candidate and other efflux and uptake transporters, as required by regulatory agencies, are available upon request.