ATC Group: A05A Bile therapy

Exogenous chenodeoxycholic acid is used as replacement therapy to restore the feedback inhibition lost due to the deficiency/absence of endogenous chenodeoxycholic acid. In CTX, deficiency of chenodeoxycholic acid causes a lack of feedback of cholesterol 7 alpha hydroxylase (CYP7A1) and HMG CoA reductase, causing increased production of atypical bile acids, bile alcohols and cholestanol that lead to the pathological consequences of the condition.

Cholic acid is the predominant primary bile acid in man. In patients with inborn deficiency of 3β-Hydroxy-Δ⁵−C₂₇-steroid oxidoreductase and Δ⁴-3-Oxosteroid-5β-reductase, the biosynthesis of primary bile acids is reduced or absent. The rational basis for treatment consists of restoration of the bile aciddependent component of bile flow enabling restoration of biliary secretion and biliary elimination of toxic metabolites; inhibition of the production of the toxic bile acid metabolites by negative feedback on cholesterol 7α-hydroxylase, which is the rate-limiting enzyme in bile acid synthesis; and improvement of the patient’s nutritional status by correcting intestinal malabsorption of fats and fat-soluble vitamins.

Hymecromone is an inhibitor of hyaluronic acid synthesis and has a spasmolytic effect on extrahepatic bile ducts. Hymecromone is an approved prescription drug used for treating biliary spasm. This action takes place through a musculotropic mechanism, without atropinic effects. Increased choleresis is also observed without excitation of gall bladder contraction.

Maralixibat is a minimally absorbed, reversible, potent, selective inhibitor of the ileal bile acid transporter (IBAT). Maralixibat acts locally in the distal ileum to decrease the reuptake of bile acids and increase the clearance of bile acids through the colon, reducing the concentration of bile acids in the serum.

Obeticholic acid is a selective and potent agonist for the farnesoid X receptor (FXR), a nuclear receptor expressed at high levels in the liver and intestine. FXR activation decreases the intracellular hepatocyte concentrations of bile acids by suppressing de novo synthesis from cholesterol, as well as, by increasing transport of bile acids out of the hepatocytes.

Odevixibat is a reversible, potent, selective inhibitor of the ileal bile acid transporter (IBAT). Odevixibat acts locally in the distal ileum to decrease the reuptake of bile acids and increase the clearance of bile acids through the colon, reducing the concentration of bile acids in the serum. The extent of reduction of serum bile acids does not correlate with systemic PK.

Seladelpar is a peroxisome proliferator-activated receptor delta (PPARδ) agonist, or delpar. PPARδ is a nuclear receptor expressed in the liver and other tissues. PPARδ activation reduces bile acid synthesis in the liver through Fibroblast Growth Factor 21 (FGF21)-dependent downregulation of CYP7A1, the key enzyme for the synthesis of bile acids from cholesterol and by decreasing cholesterol synthesis and absorption. These actions result in lower bile acid exposure in the liver and reduced circulating bile acid levels.

The ursodeoxycholic acid converts lithogenic bile in non-lithogenic bile and gradually dissolves the cholesterol gallstones.