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Ursodeoxycholic acid

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Ursodeoxycholic acid
Clinical data
Trade namesMultiple proprietary names
Other namesUrsodiol
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 (UDCA), also known as ursodiol is one of the secondary bile acids, which are metabolic byproducts of intestinal bacteria.

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.[1]
  • For the treatment of primary biliary cholangitis (also known as primary biliary cirrhosis, PBC).[1]
  • To aim to improve bile flow in patients with cystic fibrosis (controversial[2])
  • In newborn infants with impaired bile flow[3]
  • 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.[4]

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.[5][6] A Cochrane systematic review in 2012 found no significant benefit in reducing mortality, the rate of liver transplantation, pruritus or fatigue.[7] Ursodiol is the only FDA approved drug to treat PBC but many patients do not respond; other treatments are under study.[8]

Ursodiol may be used to treat intrahepatic cholestasis of pregnancy, to relieve the symptoms of itching, to decrease infant mortality rate, and to decrease bile absorption.[9] Ursodiol is not believed to reduce maternal mortality from hemorrhage in such cases.

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.[10][11][12]

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.[13]

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.[14]

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.[15]

Recent research at the University of Sheffield indicates that Ursodeoxycholic Acid shows promise in the treatment of Alzheimer's Disease.[16][17]

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.[18]

It is believed to inhibit apoptosis.[19]

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.[20]

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.[21][22] For this reason, it has not supplanted surgical treatment by cholecystectomy.

Ursodeoxycholic acid has been shown to exert anti-inflammatory and protective effects in human epithelial cells of the gastrointestinal tract. It has been linked to regulation of immunoregulatory responses via regulation of cytokines,[23] antimicrobial peptides defensins,[24] and take an active part in increased restitution of wound in the colon.[25] Moreover, UDCA's effects has been shown to have exert actions outside the epithelial cells.[26]

Names

The term is from the Latin noun ursus meaning bear, as bear bile contains the substance.

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

See also

References

  1. ^ a b "Ursodeoxycholic acid ursodiol drug information". www.uptodate.com.
  2. ^ "Cystic fibrosis: Hepatobiliary disease". www.uptodate.com.
  3. ^ "Treatment of unconjugated hyperbilirubinemia in term and late preterm infants". www.uptodate.com.
  4. ^ Uy MC, Talingdan-Te MC, Espinosa WZ, Daez ML, Ong JP (December 2008). "Ursodeoxycholic acid in the prevention of gallstone formation after bariatric surgery: a meta-analysis". Obesity Surgery. 18 (12): 1532–8. doi:10.1007/s11695-008-9587-7. PMID 18574646.
  5. ^ Shi J, Wu C, Lin Y, Chen YX, Zhu L, Xie WF (July 2006). "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. PMID 16863557.
  6. ^ "Trials of ursodeoxycholic acid for the treatment of primary biliary cholangitis (primary biliary cirrhosis)". www.uptodate.com. Retrieved 2016-12-27.
  7. ^ Rudic JS, Poropat G, Krstic MN, Bjelakovic G, Gluud C (December 2012). "Ursodeoxycholic acid for primary biliary cirrhosis". The Cochrane Database of Systematic Reviews. 12: CD000551. doi:10.1002/14651858.CD000551.pub3. PMID 23235576.
  8. ^ 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.
  9. ^ Mayo Clinic Staff. "Cholestasis of pregnancy: Treatment and Drugs". Mayo Clinic.
  10. ^ Kotb MA (July 2008). "Review of historical cohort: ursodeoxycholic acid in extrahepatic biliary atresia". Journal of Pediatric Surgery. 43 (7): 1321–7. doi:10.1016/j.jpedsurg.2007.11.043. PMID 18639689.
  11. ^ Paediatric Formulary Committee (2008). British National Formulary for Children 2008. London: Pharmaceutical Press. p. 91. ISBN 978-0-85369-780-0.
  12. ^ "Urso package insert" (PDF). Birmingham, AL: Axcan Pharma U.S. January 2000.
  13. ^ Cheng K, Ashby D, Smyth RL (September 2017). Cochrane Cystic Fibrosis and Genetic Disorders Group (ed.). "Ursodeoxycholic acid for cystic fibrosis-related liver disease". The Cochrane Database of Systematic Reviews. 9: CD000222. doi:10.1002/14651858.CD000222.pub4. PMC 6483662. PMID 28891588.
  14. ^ Lindor KD, Kowdley KV, Luketic VA, Harrison ME, McCashland T, Befeler AS, Harnois D, Jorgensen R, Petz J, Keach J, Mooney J, Sargeant C, Braaten J, Bernard T, King D, Miceli E, Schmoll J, Hoskin T, Thapa P, Enders F (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.
  15. ^ "Ursodeoxycholic acid: serious hepatic events" (PDF). WHO Drug Information. 26 (1). 2012.
  16. ^ Cohut, Maria. "Existing liver drug can help treat Alzheimer's". Medical News Today. {{cite web}}: Unknown parameter |name-list-format= ignored (|name-list-style= suggested) (help)
  17. ^ Bell SM, Barnes K, Clemmens H, Al-Rafiah AR, Al-Ofi EA, Leech V, et al. (October 2018). "Ursodeoxycholic Acid Improves Mitochondrial Function and Redistributes Drp1 in Fibroblasts from Patients with either Sporadic or Familial Alzheimer's Disease". Journal of Molecular Biology. 430 (21): 3942–3953. doi:10.1016/j.jmb.2018.08.019. PMC 6193139. PMID 30171839.
  18. ^ 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.
  19. ^ 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)
  20. ^ Material Safety Data Sheet on Ursodiol MSDS. https://fscimage.fishersci.com/msds/70916.htm
  21. ^ "URSODEOXYCHOLIC ACID" (PDF). Public Assessment Report for paediatric studies submitted in accordance with Article 45 of Regulation (EC) No1901/2006, as amended.
  22. ^ "PUBLIC ASSESSMENT REPORT" (PDF). Medicines Evaluation Board in the Netherlands.
  23. ^ Ward JB, Lajczak NK, Kelly OB, O'Dwyer AM, Giddam AK, Ní Gabhann J, Franco P, Tambuwala MM, Jefferies CA, Keely S, Roda A, Keely SJ (June 2017). "Ursodeoxycholic acid and lithocholic acid exert anti-inflammatory actions in the colon". American Journal of Physiology. Gastrointestinal and Liver Physiology. 312 (6): G550–G558. doi:10.1152/ajpgi.00256.2016. PMID 28360029.
  24. ^ Lajczak NK, Saint-Criq V, O'Dwyer AM, Perino A, Adorini L, Schoonjans K, Keely SJ (September 2017). "Bile acids deoxycholic acid and ursodeoxycholic acid differentially regulate human β-defensin-1 and -2 secretion by colonic epithelial cells". FASEB Journal. 31 (9): 3848–3857. doi:10.1096/fj.201601365R. PMID 28487283.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  25. ^ Mroz MS, Lajczak NK, Goggins BJ, Keely S, Keely SJ (March 2018). "The bile acids, deoxycholic acid and ursodeoxycholic acid, regulate colonic epithelial wound healing". American Journal of Physiology. Gastrointestinal and Liver Physiology. 314 (3): G378–G387. doi:10.1152/ajpgi.00435.2016. PMID 29351391.
  26. ^ O'Dwyer AM, Lajczak NK, Keyes JA, Ward JB, Greene CM, Keely SJ (August 2016). "Ursodeoxycholic acid inhibits TNFα-induced IL-8 release from monocytes". American Journal of Physiology. Gastrointestinal and Liver Physiology. 311 (2): G334–41. doi:10.1152/ajpgi.00406.2015. PMID 27340129.
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