Linerixibat

The molecular mechanism of linerixibat involves the targeted inhibition of the apical sodium-dependent bile acid transporter (ASBT), also known as SLC10A2, located on the luminal membrane of ileal enterocytes. Under normal physiological conditions, ASBT is the primary vehicle for the active reabsorption of bile acids from the intestinal lumen back into the portal circulation. Linerixibat binds with high affinity to the active site of the ASBT protein, preventing the uptake of both conjugated and unconjugated bile acids. By blocking this reabsorption, linerixibat forces the excretion of bile acids into the feces. This depletion of the total bile acid pool leads to a significant reduction in the systemic levels of bile acids and other potential pruritogens that typically accumulate in cholestatic diseases like PBC. The reduction in systemic bile acids is thought to decrease the activation of TGR5 receptors and other sensory neurons in the skin that transmit the sensation of itch. At the hepatic level, the loss of returned bile acids relieves the feedback inhibition on the enzyme cholesterol 7 alpha-hydroxylase (CYP7A1), resulting in the increased conversion of hepatic cholesterol into new bile acids, which further assists in lowering systemic lipid levels.