Urlyx/Urlyx 500 Mechanism of Action

Pharmacology: Pharmacodynamics: Urlyx: Ursodeoxycholic acid is a product of metabolism of bacteria in the intestine. It is considered a secondary bile acid. The primary bile acids are produced hepatically and are stored in the gallbladder. It is released into the large intestine and is broken down into secondary bile acids by the bacteria present in the intestine. Both the primary and secondary bile acids assist in the metabolism of dietary fat. Ursodeoxycholic acid regulates cholesterol levels by slowing the rate at which the intestine is able to absorb cholesterol and to break down the micelles which contain cholesterol; this property of ursodeoxycholic acid is used in the non-surgical treatment of gallstones.
Urlyx 500: During chronic administration, Urlyx 500 becomes a major biliary and plasma bile acid. At a chronic dose of 13-15 mg/kg/day, Urlyx 500 constitutes 30-50% of biliary and plasma bile acids.
Mechanism of Action: Urlyx 500, a naturally occurring hydrophilic bile acid, derived from cholesterol, is present as a minor fraction of the total human bile acid pool. Oral administration of Urlyx 500 increases this fraction in a dose related manner, to become the major biliary acid, replacing/displacing toxic concentrations of endogenous hydrophobic bile acids that tend to accumulate in cholestatic liver disease.
Multiple mechanisms of action at the cellular and molecular level in addition to the replacement and displacement of toxic bile acids include cytoprotection of the injured bile duct epithelial cells (cholangiocytes) against toxic effects of bile acids, inhibition of apoptosis of hepatocytes, immunomodulatory effects via a number of mechanisms including decreasing expression of MHC class I proteins on hepatocytes and cholangiocytes, and stimulation of bile secretion by hepatocytes and cholangiocytes.
The cholesterol-lowering effect observed following the administration of Ursodeoxycholic acid in patients with primary biliary cirrhosis could be related to an improvement of cholestasis, modifications in cholesterol metabolism, or both. Changes in the endogenous bile acid composition induced by Ursodeoxycholic acid might be the common denominator of these two mechanisms.
Pharmacokinetics: Urlyx: Ursodeoxycholic acid is absorbed from the gastrointestinal tract and undergoes enterohepatic recycling. It is partly conjugated in the liver before being excreted into the bile. Under the influence of intestinal bacteria, the free and conjugated forms undergo 7a-dehydroxylation to lithocholic acid, some of which is excreted directly in the feces and the rest absorbed and mainly conjugated and sulfated by the liver before excretion in the feces. However, in comparison with chenodeoxycholic acid, less ursodeoxycholic acid undergoes such bacterial degradation.
Urlyx 500: Absorption: Urlyx 500 (UDCA) is normally present as a minor fraction of the total bile acids in humans (about 5%). Following oral administration, the majority of Urlyx 500 is absorbed by passive diffusion and its absorption is incomplete.
Distribution: In healthy subjects, at least 70% of ursodeoxycholic acid (unconjugated) is bound to plasma protein. No information is available on the binding of conjugated Urlyx 500 to plasma protein in healthy subjects or primary biliary cirrhosis (PBC) patients. However, since the efficacy of Urlyx 500 is related to its concentration in bile rather than in plasma, serum levels are not indicative of bioavailability in clinical settings. Its volume of distribution has not been determined, but is expected to be small since the drug is mostly distributed in the bile and small intestine. In bile, UDCA concentration reaches a peak in 1-3 hours.
Metabolism: Once absorbed, Urlyx 500 undergoes hepatic extraction to the extent of about 70% in the absence of liver disease. This leads to low blood levels in the systemic circulation. As the severity of liver disease increases, the extent of extraction decreases. In the liver, ursovis conjugated with glycine or taurine then secreted into bile. These conjugates of Urlyx 500 are absorbed in the small intestine by passive and active mechanisms. The conjugates can also be deconjugated in the ileum by intestinal enzymes, leading to the formation of free ursodiol that can be reabsorbed and reconjugated in the liver. Non absorbed Urlyx 500 passes into the colon where it is mostly 7-dehydroxylated to lithocholic acid. Some Urlyx 500 is epimerized to chenodiol (CDCA) via a 7-oxo intermediate. Chenodiol also undergoes 7-dehydroxylation to form lithocholic acid. These metabolites are poorly soluble and excreted in the feces. A small portion of lithocholic acid is reabsorbed, conjugated in the liver with glycine or taurine, and sulfated at the 3-position. The resulting sulfated lithocholic acid conjugates are excreted in bile and then lost in feces.
Lithocholic acid, when administered chronically to animals, causes cholestatic liver injury that may lead to death from liver failure in certain species unable to form sulfate conjugates. Urlyx 500 is 7-dehydroxylated more slowly, than chenodiol. For equimolar doses of Urlyx 500 and chenodiol, steady state levels of lithocholic acid in biliary bile acids are lower during Urlyx 500 administration than with chenodiol administration. Humans and chimpanzees can sulfate lithocholic acid. Although liver injury has not been associated with Urlyx 500 therapy, a reduced capacity to sulfate may exist in some individuals. Nonetheless, such a deficiency has not yet been clearly demonstrated and must be extremely rare, given the several thousand patient-years of clinical experience with Urlyx 500.
Excretion: Ursodeoxycholic Acid is excreted primarily in the feces with treatment urinary excretion increases but remains less than 1%, except in severe cholestatic liver disease.