Carrier cross-reactivities of the bile acid reabsorption inhibitors elobixibat, linerixibat, maralixibat, and odevixibat

Abstract

The bile acid reabsorption inhibitors (BARIs) elobixibat, maralixibat, and odevixibat are clinically used inhibitors of the intestinal bile acid transporter ASBT (SLC10A2). An additional BARI compound, linerixibat, is still under clinical development. In the present study, potential cross-reactivities against the closely related hepatic bile acid carrier and hepatitis B virus entry receptor NTCP (SLC10A1), as well as the steroid sulfate uptake carrier SOAT (SLC10A6) were analyzed. All BARIs potently inhibited ASBT (IC50 = 0.1–1.0 μM). Among them, elobixibat, maralixibat, and odevixibat also inhibited SOAT (IC50 = 3.2–5.9 μM) and NTCP (IC50 = 10–99 μM). Furthermore, all four BARIs inhibited the hepatic drug transporters OATP1B1, OATP1B3, and OATP2B1 (IC50 = 1.6–29 μM). Notably, ASBT inhibition by linerixibat was reversible upon washout, while maralixibat and odevixibat induced full and sustained ASBT inhibition even after removal of the inhibitor and inhibitor-free incubation over 240 min. Elobixibat and the pan-SLC10 inhibitor troglitazone revealed an intermediate effect. The ASBT S294T/I295V double mutation increased the inhibitory potency of linerixibat, suggesting a role of this domain for linerixibat binding. In contrast, this mutation had no significant effect on the ASBT inhibition by elobixibat, maralixibat, and odevixibat, indicating distinct binding sites. In conclusion, the analyzed BARIs revealed carrier cross-reactivities with NTCP, SOAT, and members of the OATP family, but behaved differently regarding their time-dependent inhibition and potential inhibitor binding sites.