Membrane drug transporters, located in many barrier tissues in the body, may interact with drugs to affect absorption, distribution and elimination in vivo, and are the cause of clinically relevant drug-drug interactions (DDIs). Identification of the test article as a substrate or an inhibitor of transporters can explain clinically relevant altered exposures and toxicities of concomitantly administered drugs.
Intestinal permeability of a drug is an important factor driving the fraction absorbed and can be evaluated using the Caco-2 monolayer transport assay.
Regulatory considerations for transporter interactions
These studies are recommended by both FDA and EMA drug-drug interaction (DDI) guidelines to evaluate transporter interactions before going into first-in-human trials. Transporter studies highlight potential issues with achieving efficacious plasma concentrations of concomitantly administered medications due to a drug's impact on absorption or distribution.
Several transporters interact with drugs in clinical use. Those recommended for testing include:
- ATP binding cassette (ABC) efflux transporters P-glycprotein (P-gp), Breast Cancer Resistance Protein (BCRP), and Bile Salt Export Pump (BSEP).
- Solute carrier (SLC) uptake transporters Organic Anion Transporter (OAT) 1 and OAT3, Organic Cation Transporter (OCT) 2, Organic Anion Transporting Polypeptide (OATP) 1B1, OATP1B3, and Multidrug and Toxin Extrusion (MATE) 1 and MATE2 K.