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Ursodeoxycholic acid (UDCA) is a major effective constituent of bear bile powder, which is widely used as function food in China and is documented in the Chinese pharmacopoeia as a traditional Chinese medicine. UDCA has been developed as the only accepted therapy by the US FDA for primary biliary cholangitis. Recently, the US FDA granted accelerated approval to obeticholic acid (OCA), a semisynthetic bile acid derivative from chenodeoxycholic acid, for primary biliary cholangitis. However, some perplexing toxicities of UDCA have been reported in the clinic. The present work aimed to investigate the difference between UDCA and OCA in regard to potential metabolic activation through acyl glucuronidation and hepatic accumulation of consequent acyl glucuronides. Our results demonstrated that the metabolic fates of UDCA and OCA were similar. Both UDCA and OCA were predominantly metabolically activated by conjugation to the acyl glucuronide in human liver microsomes. UGT1A3 played a predominant role in the carboxyl glucuronidation of both UDCA and OCA, while UGT2B7 played a major role in their hydroxyl glucuronidation. Further uptake studies revealed that OATP1B1- and 1B3-transfected cells could selectively uptake UDCA acyl glucuronide, but not UDCA, OCA, and OCA acyl glucuronide. In summary, the liver disposition of OCA is different from that of UDCA due to hepatic uptake, and liver accumulation of UDCA acyl glucuronide might be related to the perplexing toxicities of UDCA.
This article was published in the following journal.
Name: Chemico-biological interactions
Ursodeoxycholic acid (UDCA) is the first-line treatment for primary biliary cholangitis, but its effects on bile acid (BA) enterohepatic circulation have been under-investigated. Therefore, we intende...
This review will summarize the use of obeticholic acid (OCA) in treatment of primary biliary cholangitis (PBC). It seeks to discuss the mechanism of action, evidence for use, appropriate clinical use,...
To evaluate the contribution of ursodeoxycholic acid (UDCA) in the first 12 months after Roux-en-Y gastric bypass in the prevention of gallstone formation.
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20 patients presenting a rhegmatogenous retinal detachment with more than 4 days of duration will be prospectively included. A single dose of ursodeoxycholic acid will be administered ora...
An epimer of chenodeoxycholic acid. It is a mammalian bile acid found first in the bear and is apparently either a precursor or a product of chenodeoxycholate. Its administration changes the composition of bile and may dissolve gallstones. It is used as a cholagogue and choleretic.
A family of POTASSIUM and SODIUM-dependent acidic amino acid transporters that demonstrate a high affinity for GLUTAMIC ACID and ASPARTIC ACID. Several variants of this system are found in neuronal tissue.
A family of enzymes that catalyze the stereoselective, regioselective, or chemoselective syn-dehydrogenation reactions. They function by a mechanism that is linked directly to reduction of molecular OXYGEN.
A sodium-dependent neutral amino acid transporter that accounts for most of the sodium-dependent neutral amino acid uptake by mammalian cells. The preferred substrates for this transporter system include ALANINE; SERINE; and GLUTAMINE.
A monocarboxylic acid anion derived from selective deprotonation of the carboxy group of phosphoenolpyruvic acid. It is a metabolic intermediate in GLYCOLYSIS; GLUCONEOGENESIS; and other pathways.
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