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Transporters

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An increasing body of evidence suggests that the role of transporters in the absorption, distribution, and excretion of drugs as well as in pharmacology, toxicology and drug-drug interactions (DDIs) may be significant. Regulatory agencies are increasingly focusing on these potential transporter-mediated DDIs. The molecular and functional characterisation of transport proteins is emerging rapidly and significant numbers of drugs have been shown to be substrates or inhibitors.

Two major groups of proteins are involved in drug transport. The first includes multispecific solute carrier (SLC) transporters, facilitating the cellular entry or exit of a wide range of compounds. In the liver, transport proteins are present on the sinusoidal membrane that can be the rate-limiting step in hepatic clearance for some drugs. Mechanistic studies clearly suggest a key role and broad substrate specificity for the SLC family.

The second major group of transporters are the multidrug resistance (MDR) ATP binding cassette (ABC) proteins. They play an important role in cancer drug resistance, protection against xenobiotics, and in the passage of drugs through cellular and tissue barriers. For absorption, a clear role has emerged for P-glycoprotein (Pgp) in limiting permeability across the gastrointestinal tract. Pgp and MRP2 govern also active biliary excretion. Similarly, at the blood-brain barrier a range of drugs has limited brain penetration due to Pgb-mediated efflux, which can limit therapeutic effectiveness of CNS agents.

In drug discovery, key challenges are to choose the most appropriate and convenient assay, and to implement and validate the results. According to the current guidelines of the FDA, such investigations should be performed in the early stage of drug development, using ‘suitable in vitro probes’. For predicting in vivo drug–transporter interactions, the FDA recommends cell-based transport assays, such as Caco-2 and Pgp-transfected forms of the MDCK or LLC-PK1 cells.

List of transporters,
their substrates & inhibitors

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