Drug transporters are increasingly being implicated as a source of drug-drug interactions (DDI) and potential organ-specific toxicity in humans. Consequently interactions with these membrane bound proteins are of increasing importantance to assess during drug development, as recent Regulatory draft guidance reflects. In vitro technology is rapidly advancing in the field of drug transporter interactions and this information is now an integral component of modern DDI assessment.

 

+ Drug transporters may be classified into two broad types based upon their primary
functionality;  either drug uptake or drug efflux:

– Uptake transporters – OATP, OAT, OCT, MATE - Transport molecules into the cell and so are therefore generally located on the basal membrane of cells. Uptake transporters generally operate with a concentration gradient and so, typically, do not require an energy source (such as ATP) to operate.

– Efflux transporters – MDR1 (P-gp), BCRP. MRP - Transport molecules out of cells and so are therefore generally located on the apical embrane of cells. Efflux transporters typically operate against a concentration gradient and so generally require an energy source, which is normally provided by the hydrolysis of intracellular ATP.

+ In addition to potential transporter-mediated DDIs, for drug development, it is crucial to understand how new drug candidates interact with membrane transporters, both as a substrate and as a potential inhibitor to assist in the understanding of intracellular drug concentrations and organ tissue uptake and distribution and potential organ-specific toxicity.

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