Cholemax Mechanism of Action

Pharmacotherapeutic group: Bile Acid Preparation. ATC code: A05AA02 and A05B.
Pharmacology: Pharmacodynamics: Capsule: Ursodeoxycholic acid, the 7-β-hydroxyepimer of chenodeoxycholic acid (chenodiol), is a naturally occurring, hydrophilic bile acid found in small quantities in normal human bile (normally about 5% of total bile acids) and in the bile of certain animals.
The exact mechanism of action(s) of ursodeoxycholic acid in the dissolution of gallstones has not been fully elucidated, but it has been suggested that the drug suppresses hepatic synthesis and secretion of cholesterol and inhibits intestinal absorption of cholesterol.
Despite aqueous insolubility of cholesterol, in the presence of dihydroxy bile acids cholesterol can be solubilized in aqueous media through the dispersion of cholesterol as liquid crystals or micelles.
Appear to have small inhibitory effect on synthesis and secretion of endogenous bile acids into bile, does not appear to affect secretion of phospholipids into bile.
Site of therapeutic action include the liver, bile and gut lumen.
In patients with gallstones, combined actions of ursodeoxycholic acid change the bile from cholesterol-precipitating to cholesterol-solubilizing, which results in dissolution of cholesterol stones.
Oral suspension: UDCA is a bile acid which effects a reduction in cholesterol in biliary fluid primarily by dispersing the cholesterol and forming a liquid-crystal phase. UDCA affects the enterohepatic circulation of bile salts by reducing the ileal reabsorption of endogenous more hydrophobic and potentially toxic salts such as cholic and chenodeoxycholic acids.
In-vitro studies show that UDCA has a direct hepatoprotective effect and reduces the hepatotoxicity of hydrophobic bile salts. Immunological effects have also been demonstrated with a reduction in abnormal expression of HLS Class I antigens on hepatocytes as well as suppression of cytokine and interleukin production.
Cystic fibrosis - Paediatric population: From clinical reports long-term experience up to 10 years and more is available with UDCA treatment in paediatric patients suffering from cystic fibrosis associated hepatobiliary disorders (CFAHD). There is evidence that treatment with UDCA can decrease bile duct proliferation, halt progression of histological damage and even reverse hepatobiliary changes if given at early stage of CFAHD. Treatment with UDCA should be started as soon as the diagnosis of CFAHD is made in order to optimise treatment effectiveness.
Pharmacokinetics: Capsule: About 90% of a therapeutic dose of ursodeoxycholic acid is absorbed in the small bowel after oral administration. After absorption, ursodeoxycholic acid enters the portal vein and undergoes efficient extraction from portal blood by the liver (there is a large "first-pass" effect) where it is conjugated with either glycine or taurine and is then secreted into the hepatic bile ducts. Ursodeoxycholic acid in bile is concentrated in the gallbladder and expelled into the duodenum in gallbladder bile via the cystic and common ducts by gallbladder contractions provoked by physiologic responses to eating. Only small quantities of ursodeoxycholic acid appear in the systemic circulation and very small amounts are excreted into urine. The sites of the drug's therapeutic actions are in the liver, bile, and gut lumen. With repeated dosing, bile ursodeoxycholic acid concentrations reach steady state in about 3 weeks.
Beyond conjugation, ursodeoxycholic acid is not altered or catabolized appreciably by the liver or intestinal mucosa. Ursodeoxycholic acid can be both oxidized and reduced at the 7- carbon, yielding either 7-keto-lithocholic acid or lithocholic acid, respectively. Free ursodeoxycholic acid, 7-keto-lithocholic acid, and lithocholic acid are relatively insoluble in aqueous media and larger proportions of these compounds are lost from the distal gut into the feces. Reabsorbed free ursodeoxycholic acid is reconjugated by the liver. Eighty percent (80%) of lithocholic acid formed in the small bowel is excreted in the feces, but the 20% that is absorbed is sulfated at the 3-hydroxyl group in the liver to insoluble lithocholyl conjugates that are excreted into bile and lost in feces.
Oral suspension: UDCA occurs naturally in the body. When given orally it is rapidly and completely absorbed. It is 96-98% bound to plasma proteins and efficiently extracted by the liver and excreted in the bile as glycine and taurine conjugates. In the intestine some of the conjugates are deconjugated and reabsorbed. The conjugates may also be dehydroxylated to lithocholic acid, part of which is absorbed, sulphated by the liver and excreted via the biliary tract.
Toxicology: Preclinical safety data: Oral suspension: Acute toxicity: Acute toxicity studies in animals have not revealed any toxic damage.
Chronic toxicity: Subchronic toxicity studies in monkeys showed hepatotoxic effects in the groups given high doses, including functional changes (e.g. liver enzyme changes) and morphological changes such as bile duct proliferation, portal inflammatory foci and hepatocellular necrosis. These toxic effects are most likely attributable to lithocholic acid, a metabolite of UDCA, which in monkeys unlike humans is not detoxified. Clinical experience confirms that the described hepatotoxic effects are of no apparent relevance in humans.
Carcinogenic and mutagenic potential: Long-term studies in mice and rats revealed no evidence of UDCA having carcinogenic potential.
In vitro and in vivo genetic toxicology tests with UDCA were negative.
The tests with UDCA revealed no relevant evidence of a mutagenic effect.
Toxicity to reproduction: In studies in rats, tail malformations occurred after a dose of 2000 mg of UDCA per kg of body weight. In rabbits, no teratogenic effects were found, although there were embryotoxic effects (from a dose of 100 mg per kg of body weight). UDCA had no effect on fertility in rats and did not affect peri-/post-natal development of the offspring.