Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

12.1 Mechanism of Action

Cholic acid is a primary bile acid synthesized from cholesterol in the liver. In bile acid synthesis disorders due to SEDs in the biosynthetic pathway, and in PDs including Zellweger spectrum disorders, deficiency of primary bile acids leads to unregulated accumulation of intermediate bile acids and cholestasis. Bile acids facilitate fat digestion and absorption by forming mixed micelles and facilitate absorption of fat-soluble vitamins in the intestine.

Endogenous bile acids including cholic acid enhance bile flow and provide the physiologic feedback inhibition of bile acid synthesis. The mechanism of action of cholic acid has not been fully established; however, it is known that cholic acid and its conjugates are endogenous ligands of the nuclear receptor, farnesoid X receptor (FXR). FXR regulates enzymes and transporters that are involved in bile acid synthesis and in the enterohepatic circulation to maintain bile acid homeostasis under normal physiologic conditions.

Pharmacokinetic Properties

12.2 Pharmacokinetics

Orally administered cholic acid is subject to the same metabolic pathway as endogenous cholic acid.

Cholic acid is absorbed by passive diffusion along the length of the gastrointestinal tract. Once absorbed, cholic acid enters into the body’s bile acid pool and undergoes enterohepatic circulation mainly in conjugated forms.

In the liver, cholic acid is conjugated with glycine or taurine by bile acid-CoA synthetase and bile acid- CoA:amino acid N-acyltransferase. Conjugated cholic acid is actively secreted into bile by the BSEP, and then released into the small intestines, along with other components of bile.

Conjugated cholic acid is mostly re-absorbed in the ileum mainly by the apical-sodium-dependent-bile acid transporter, passed back to the liver by transporters including sodium-taurocholate cotransporting polypeptide and organic anion transport protein and enters another cycle of enterohepatic circulation.
Any conjugated cholic acid not absorbed in the ileum passes into the colon where deconjugation and 7- dehydroxylation are mediated by bacteria to form cholic acid and deoxycholic acid, which may be re- absorbed in the colon or excreted in the feces. The loss of cholic acid is compensated by de-novo synthesis of cholic acids from cholesterol to maintain the bile acid pool in healthy subjects.