Ursodeoxycholic acid

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Ursodeoxycholic acid
Clinical data
Trade namesActigall, Udcasid, others
Other namesursodeoxycholic acid, Actigall, Ursosan, Urso, Urso Forte
AHFS/Drugs.comMonograph
MedlinePlusa699047
License data
Pregnancy
category
  • AU: B3
Routes of
administration		oral
ATC code
Legal status
Legal status
Identifiers
  • 3α,7β-dihydroxy-5β-cholan-24-oic acid
    OR
    (R)-4-((3R,5S,7S,8R,9S,10S,13R,14S,17R)-3,7-dihydroxy-
    10,13-dimethylhexadecahydro-
    1H-cyclopenta[a]phenanthren-17-yl)pentanoic acid
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
PDB ligand
CompTox Dashboard (EPA)
ECHA InfoCard100.004.437 Edit this at Wikidata
Chemical and physical data
FormulaC24H40O4
Molar mass392.56 g/mol g·mol−1
3D model (JSmol)
Melting point203 °C (397 °F)
  • O=C(O)CC[C@H]([C@H]1CC[C@@H]2[C@]1(C)CC[C@H]4[C@H]2[C@@H](O)C[C@@H]3C[C@H](O)CC[C@@]34C)C
  • InChI=1S/C24H40O4/c1-14(4-7-21(27)28)17-5-6-18-22-19(9-11-24(17,18)3)23(2)10-8-16(25)12-15(23)13-20(22)26/h14-20,22,25-26H,4-13H2,1-3H3,(H,27,28)/t14-,15+,16-,17-,18+,19+,20+,22+,23+,24-/m1/s1 checkY
  • Key:RUDATBOHQWOJDD-UZVSRGJWSA-N checkY
  (verify)

Ursodeoxycholic acid (INN, BAN and AAN), also known as ursodiol (USAN) and the abbreviation UDCA, from the root-word for bear urso, as bear bile contains the substance, is one of the secondary bile acids, which are metabolic byproducts of intestinal bacteria.

Endogenous effects

Primary bile acids are produced by the liver and stored in the gall bladder. When secreted into the intestine, primary bile acids can be metabolized into secondary bile acids by intestinal bacteria. Primary and secondary bile acids help the body digest fats. Ursodeoxycholic acid helps regulate cholesterol by reducing the rate at which the intestine absorbs cholesterol molecules while breaking up micelles containing cholesterol. Because of this property, ursodeoxycholic acid is used to treat (cholesterol) gallstones non-surgically. It is also used to relieve itching in pregnancy for some women who suffer obstetric cholestasis.

While some bile acids are known to be colon tumor promoters (e.g. deoxycholic acid), others such as ursodeoxycholic acid are thought to be chemopreventive, perhaps by inducing cellular differentiation and/or cellular senescence in colon epithelial cells.[1]

It is believed to inhibit apoptosis.[2]

Ursodeoxycholic acid has also been shown experimentally to suppress immune response such as immune cell phagocytosis. Prolonged exposure and/or increased quantities of systemic (throughout the body, not just in the digestive system) ursodeoxycholic acid can be toxic.[3]

Medical uses

An incomplete list of the current uses is as follows:

  • Reduction in gallstone formation, either in patients with gallstones unfit for cholecystectomy, or obese patients undergoing rapid weight loss to prevent gallstone formation.[4]
  • For the treatment of primary biliary cholangitis (also known as primary biliary cirrhosis, PBC).[4]
  • To aim to improve bile flow in patients with cystic fibrosis (controversial[5])
  • In newborn infants with impaired bile flow[6]
  • After bariatric surgery, to prevent cholelithiasis due to the rapid weight loss with biliary cholesterol oversaturation and also biliary diskinesia secondary to abnormalities in cholecystokinin and biliary enervation.[7]

Meta-analyses have borne out conflicting results on the mortality benefit of UDCA in PBC, however analyses that exclude trials of short duration (i.e. < 2 years) have demonstrated a survival benefit and are generally considered more clinically relevant.[8][9] A Cochrane systematic review in 2012 found no significant benefit in reducing mortality, the rate of liver transplantation, pruritus or fatigue.[10] Ursodiol is the only FDA approved drug to treat PBC but many patients do not respond; other treatments are under study.[11]

Ursodiol may be used for biliary stasis, [also known as intrahepatic cholestasis of pregnancy, to relieve the symptoms of itching, and to decrease infant mortality rate, which is generally believed to be 10% when Urso is not administered in this fairly rare, and largely undiagnosed pregnancy related disorder. Maternal mortality from hemorrhage is another outcome of the disease, but Urso is not believed to be the preventive cure for this outcome], and to decrease bile absorption.[12]

In children, ursodeoxycholic acid use is not licensed, as its safety and effectiveness have not been established. Evidence is accumulating that ursodeoxycholic acid is ineffective and unsafe in neonatal hepatitis and neonatal cholestasis.[13][14][15]

There is insufficient evidence to justify routine use of ursodeoxycholic acid in cystic fibrosis, especially that available data for analysis of long-term outcomes such as death or need for liver transplantation is lacking.[16]

In double the recommended daily dose ursodeoxycholic acid reduces elevated liver enzyme levels in those with primary sclerosing cholangitis, but its use was associated with an increased risk of serious adverse events (the development of cirrhosis, varices, death or liver transplantation) in patients who received ursodeoxycholic acid compared with those who received placebo. Serious adverse events, were more common in the ursodeoxycholic acid group than the placebo group. The risk was 2.1 times greater for death, transplantation, or minimal listing criteria in patients on ursodeoxycholic acid than for those on placebo.[17]

It is concluded that ursodeoxycholic acid use is associated with improved serum liver tests that do not always correlate with improved liver disease status. WHO Drug Information advises against its use in primary sclerosing cholangitis in unapproved doses beyond 13–15 mg/kg/day.[18]

Mechanism of action

The drug reduces cholesterol absorption and is used to dissolve (cholesterol) gallstones in patients who want an alternative to surgery. If the patient stops taking the drug the gallstones tend to recur if the condition that gave rise to their formation does not change.[19][20] For these reasons, it has not supplanted surgical treatment by cholecystectomy.

Also used to relieve itching in intrahepatic cholestasis of pregnancy (naltrexone may also be used).

Trade names

Ursodeoxycholic acid can be chemically synthesized and is marketed under multiple trade names, including Actibile, Actigall, Biliver, Deursil, Egyurso, Udcasid, Udiliv, Udoxyl, Urso, Urso Forte, Ursocol, Ursoliv, Ursofalk, Ursosan, Ursoserinox, Udimarin, Ursonova, and Stenerh.

See also

References

  1. ^ Akare S, Jean-Louis S, Chen W, Wood DJ, Powell AA, Martinez JD (December 2006). "Ursodeoxycholic acid modulates histone acetylation and induces differentiation and senescence". International Journal of Cancer. 119 (12): 2958–69. doi:10.1002/ijc.22231. PMID 17019713.
  2. ^ Amaral JD, Viana RJ, Ramalho RM, Steer CJ, Rodrigues CM (September 2009). "Bile acids: regulation of apoptosis by ursodeoxycholic acid". Journal of Lipid Research. 50 (9): 1721–34. doi:10.1194/jlr.R900011-JLR200. PMC 2724780. PMID 19417220.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  3. ^ Material Safety Data Sheet on Ursodiol MSDS. https://fscimage.fishersci.com/msds/70916.htm
  4. ^ a b "Ursodeoxycholic acid ursodiol drug information". www.uptodate.com.
  5. ^ "Cystic fibrosis: Hepatobiliary disease". www.uptodate.com.
  6. ^ "Treatment of unconjugated hyperbilirubinemia in term and late preterm infants". www.uptodate.com.
  7. ^ Uy, Manley C.; Talingdan-Te, Marilyn C.; Espinosa, Wendell Z.; Daez, Ma Lourdes O.; Ong, Janus P. (1 December 2008). "Ursodeoxycholic acid in the prevention of gallstone formation after bariatric surgery: a meta-analysis". Obesity Surgery. 18 (12): 1532–1538. doi:10.1007/s11695-008-9587-7. PMID 18574646.
  8. ^ Shi, Jian; Wu, Cheng; Lin, Yong; Chen, Yue-Xiang; Zhu, Liang; Xie, Wei-fen (2006-07-01). "Long-term effects of mid-dose ursodeoxycholic acid in primary biliary cirrhosis: a meta-analysis of randomized controlled trials". The American Journal of Gastroenterology. 101 (7): 1529–38. doi:10.1111/j.1572-0241.2006.00634.x. ISSN 0002-9270. PMID 16863557.
  9. ^ "Trials of ursodeoxycholic acid for the treatment of primary biliary cholangitis (primary biliary cirrhosis)". www.uptodate.com. Retrieved 2016-12-27.
  10. ^ Rudic, JS; Poropat, G; Krstic, MN; Bjelakovic, G; Gluud, C (12 December 2012). "Ursodeoxycholic acid for primary biliary cirrhosis". The Cochrane Database of Systematic Reviews. 12: CD000551. doi:10.1002/14651858.CD000551.pub3. PMID 23235576.
  11. ^ Bowlus, CL; Kenney, JT; Rice, G; Navarro, R (October 2016). "Primary Biliary Cholangitis: Medical and Specialty Pharmacy Management Update". Journal of managed care & specialty pharmacy. 22 (10-a-s Suppl): S3–S15. doi:10.18553/jmcp.2016.22.10-a-s.s3. PMID 27700211.
  12. ^ Mayo Clinic Staff. "Cholestasis of pregnancy: Treatment and Drugs". Mayo Clinic.
  13. ^ Kotb MA (July 2008). "Review of historical cohort: ursodeoxycholic acid in extrahepatic biliary atresia". Journal of Pediatric Surgery. 43 (7): 1321–27. doi:10.1016/j.jpedsurg.2007.11.043. PMID 18639689.
  14. ^ Paediatric Formulary Committee (2008). British National Formulary for Children 2008. London: Pharmaceutical Press. p. 91. ISBN 0-85369-780-9.
  15. ^ Urso package insert. Birmingham, AL: Axcan Pharma U.S.; 2000 Jan.http://www.axcan.com/pdf/urso_patient_brochure.pdf
  16. ^ Cheng K, Ashby D, Smyth RL (Dec 2014). "Ursodeoxycholic acid for cystic fibrosis-related liver disease". Cochrane Database Syst Rev. 12: CD000222. doi:10.1002/14651858.CD000222.pub3. PMID 25501301.
  17. ^ Lindor KD; Kowdley KV; Luketic VA; et al. (September 2009). "High-dose ursodeoxycholic acid for the treatment of primary sclerosing cholangitis". Hepatology. 50 (3): 808–14. doi:10.1002/hep.23082. PMC 2758780. PMID 19585548. {{cite journal}}: Unknown parameter |name-list-format= ignored (|name-list-style= suggested) (help)
  18. ^ http://www.who.int/medicines/publications/druginformation/issues/26-1.pdf
  19. ^ Public Assessment Report for paediatric studies submitted in accordance with Article 45 of Regulation (EC) No1901/2006, as amended http://www.google.com.eg/search?q=public+MAH+UDCA&hl=en-EG&gbv=2&oq=&gs_l=
  20. ^ PUBLIC ASSESSMENT REPORT of the Medicines Evaluation Board in the Netherlands http://mri.medagencies.org/download/NL_H_2516_001_PAR.pdf

External links

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