Why ABC transporter testing matters in DMPK programs

ABC (ATP-binding cassette) transporters mediate the efflux of drugs and metabolites across cell membranes, and inhibition of key transporters — particularly BSEP, BCRP and P-gp — is mechanistically linked to drug-induced liver injury (DILI) and clinically relevant drug-drug interactions (DDI). FDA and EMA guidance both recommend transporter inhibition testing as part of standard DMPK characterisation.

The vesicle-based assay format uses HEK293-derived inside-out membrane vesicles with confirmed transporter expression, allowing direct measurement of transporter-mediated substrate uptake in the presence and absence of test compounds — the basis for IC50 determination and single-concentration screening.

Because inhibition of multiple transporters can compound DILI risk — for example, BSEP inhibition together with MRP2, MRP3 or MRP4 impairs the compensatory bile acid efflux pathways that partially protect hepatocytes — a full panel typically gives a more complete risk picture than testing BSEP in isolation.