Ursodeoxycholic acid explained

Verifiedrevid:470620651
Width:300
Width2:300
Tradename:Actigall, Urso, others
Dailymedid:Ursodiol
Pregnancy Au:B3
Pregnancy Au Comment:[1]
Routes Of Administration:By mouth
Atc Prefix:A05
Atc Suffix:AA02
Legal Au:S4
Legal Au Comment:[2]
Legal Ca:Rx-only
Legal Ca Comment:[3] [4]
Legal Uk:POM
Legal Uk Comment:[5]
Legal Us:Rx-only
Legal Us Comment:[6] [7]
Legal Status:Rx-only
Cas Number:128-13-2
Pubchem:31401
Iuphar Ligand:7104
Drugbank:DB01586
Chemspiderid:29131
Unii:724L30Y2QR
Kegg:D00734
Chebi:9907
Chembl:1551
Pdb Ligand:IU5
Synonyms:Ursodiol
Iupac Name: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
C:24
H:40
O:4
Smiles: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
Stdinchi: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
Stdinchikey:RUDATBOHQWOJDD-UZVSRGJWSA-N
Melting Point:203

Ursodeoxycholic acid (UDCA), also known as ursodiol, is a secondary bile acid, produced in humans and most other species from metabolism by intestinal bacteria. It is synthesized in the liver in some species, and was first identified in bile of bears of genus Ursus, from which its name derived.[8] In purified form, it has been used to treat or prevent several diseases of the liver or bile ducts.

It is available as a generic medication.[9] [10]

Medical uses

UDCA has been used as medical therapy in gallstone disease (cholelithiasis) and for biliary sludge.[11] [12] UDCA helps reduce the cholesterol saturation of bile and leads to gradual dissolution of cholesterol-rich gallstones.[11]

UDCA may be given after bariatric surgery to prevent cholelithiasis, which commonly occurs due to the rapid weight loss producing biliary cholesterol oversaturation and also biliary dyskinesia secondary to hormonal changes.[13]

Primary biliary cholangitis

UDCA is used as therapy in primary biliary cholangitis (PBC; previously known as primary biliary cirrhosis) where it can produce an improvement in biomarkers.[14] Meta-analyses have borne out conflicting results on the mortality benefit.[15] However analyses that exclude trials of short duration (i.e. < 2 years) have demonstrated a survival benefit and are generally considered more clinically relevant.[16] A Cochrane systematic review in 2012 found no significant benefit in reducing mortality, the rate of liver transplantation, pruritus or fatigue.[17] Ursodiol and obeticholic acid are FDA-approved for the treatment of primary biliary cholangitis.[18]

Primary sclerosing cholangitis

UDCA use is associated with improved serum liver tests that do not always correlate with improved liver disease status.[19] WHO Drug Information advises against its use in primary sclerosing cholangitis in unapproved doses beyond 13–15 mg/kg/day.[20]

UDCA in a dose of 28–30 mg/kg/day increases risk of death and need for liver transplant by 2.3-fold among those with primary sclerosing cholangitis, despite decrease in liver enzymes.[21]

Intrahepatic cholestasis of pregnancy

UDCA has been used for intrahepatic cholestasis of pregnancy. UDCA lessens itching in the mother and may reduce the number of preterm births. Effects on fetal distress and other adverse outcomes are unlikely to be great.[22] [23]

Cholestasis

UDCA use is not licensed in children, as its safety and effectiveness have not been established. Evidence is accumulating that ursodeoxycholic acid is ineffective, unsafe and its use is associated with significant risk of morbidity and mortality in neonatal hepatitis and neonatal cholestasis.[24] [25] [26] [27]

Other conditions

UDCA has been suggested to be an adequate treatment of bile reflux gastritis.[28]

In cystic fibrosis there is insufficient evidence to justify routine use of UDCA, especially as there is a lack of available data for long-term outcomes such as death or need for liver transplantation.[29]

UDCA has also been in effective in non-alcoholic fatty liver disease, in liver bile duct-paucity syndromes. It is contraindicated in obstruction of biliary tracts such as biliary atresia. It is not effective in liver allograft rejection, and in Graft-versus-host disease involving the liver.

Adverse effects

Diarrhea was the most frequent adverse event seen in trial of UDCA in gallstone dissolution, occurring in 2 to 9%, which is less frequent than with chenodeoxycholic acid therapy. Bacterial conversion of UDCA to chenodeoxycholic acid may be the mechanism for this side effect. Right upper quadrant abdominal pain and exacerbation of pruritus was occasionally reported in trials in patients with PBC.[30] Additional symptoms may include bloating, weight gain, and occasionally, thinning of hair.[31]

Mechanisms of action

Choleretic 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. The drug reduces cholesterol absorption and is used to dissolve (cholesterol) gallstones in patients who want an alternative to surgery.[32] There are multiple mechanisms involved in cholestatic liver diseases.[33]

Immunomodulating effects

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.[34]

Anti-inflammatory effects

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 by regulation of cytokines,[35] antimicrobial peptides defensins,[36] and take an active part in increased restitution of wound in the colon.[37] Moreover, UDCA's effects has been shown to have exert actions outside the epithelial cells.[38]

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.[39]

Chemistry

Ursodeoxycholic acid is an epimer of chenodeoxycholic acid, which has similar choleretic effects and a wider species distribution. However, CDCA is not as well-tolerated in humans and it does not show immunomodulating or chemoprotective effects. Both are 7-hydroxyl derivatives of deoxycholic acid, but UDCA has the group in the beta instead of the alpha orientation.

Biosynthesis

Among mammals, only bears (Ursidae; excluding giant pandas) produce UDCA at useful amounts (>30%). It is produced in the bear liver, but the pathway remains unknown.

Other vertebrates produce UDCA in much smaller amounts by gut bacteria. CDCA is oxidized into 7-oxo-CDCA then reduced into UDCA.[40]

Industrial production

UDCA is most commonly produced from cholic acid (CA) derived from bovine bile, a by-product of the beef industry. The current yield of this semisynthesis is about 30%.[41]

Society and culture

Names

The term is from the Latin noun ursus meaning bear, as bear bile contains the substance.[8]

Ursodeoxycholic acid can be chemically synthesized and is marketed under multiple trade names, including Ursetor, Udikast, Actibile, Actigall, Biliver, Deursil, Egyurso, Heptiza 300/150, Stener, Udcasid, Udiliv, Udinorm, Udoxyl, Urso, Urso Forte, Ursocol, Ursoliv, Ursofalk, Ursosan, Ursoserinox, Udimarin, and Ursonova.

History

Bear bile, a natural source of UDCA, is used in traditional Chinese medicine since the seventh century. Japanese scientists successfully synthesized UDCA chemically in 1955.[42] The earliest reference to UDCA in PubMed dates to 1957 under an alternative spelling "ursodesoxycholic acid", in a small-scale clinical trial.[43]

Ursodeoxycholic acid (application filed by Allergan) was approved for use in the United States in December 1987,[44] and was designated an orphan drug.[45]

Notes and References

  1. Web site: Ursodiol, Heptiza 300/150 Use During Pregnancy . Drugs.com . 4 November 2019 . 20 February 2020.
  2. Web site: Prescription medicines: registration of new generic medicines and biosimilar medicines, 2017 . Therapeutic Goods Administration (TGA) . 21 June 2022 . 30 March 2024.
  3. Web site: Product information . . 3 August 2000 . 3 March 2024.
  4. Web site: Details for: Ursodiol C . . 25 October 2021 . 3 March 2024.
  5. Web site: Ursodeoxycholic acid 300mg Tablets - Summary of Product Characteristics (SmPC) . (emc) . 10 July 2019 . 29 April 2020.
  6. Web site: Actigall- ursodiol capsule . DailyMed . 25 September 2021.
  7. Web site: Urso 250- ursodiol tablet, film coated Urso Forte- ursodiol tablet, film coated . DailyMed . 25 September 2021.
  8. Hagey LR, Crombie DL, Espinosa E, Carey MC, Igimi H, Hofmann AF . Ursodeoxycholic acid in the Ursidae: biliary bile acids of bears, pandas, and related carnivores . Journal of Lipid Research . 34 . 11 . 1911–1917 . November 1993 . 8263415 . 10.1016/S0022-2275(20)35109-9 . free .
  9. Web site: 2020 First Generic Drug Approvals . U.S. Food and Drug Administration (FDA) . 23 February 2021 . 25 September 2021.
  10. Web site: Ursodiol: FDA-Approved Drugs . U.S. Food and Drug Administration (FDA) . 25 September 2021.
  11. Hofmann AF . Medical dissolution of gallstones by oral bile acid therapy . American Journal of Surgery . 158 . 3 . 198–204 . September 1989 . 2672842 . 10.1016/0002-9610(89)90252-3 .
  12. Jüngst C, Kullak-Ublick GA, Jüngst D . Gallstone disease: Microlithiasis and sludge . Best Practice & Research. Clinical Gastroenterology . 20 . 6 . 1053–1062 . 2006 . 17127187 . 10.1016/j.bpg.2006.03.007 .
  13. Magouliotis DE, Tasiopoulou VS, Svokos AA, Svokos KA, Chatedaki C, Sioka E, Zacharoulis D . Ursodeoxycholic Acid in the Prevention of Gallstone Formation After Bariatric Surgery: an Updated Systematic Review and Meta-analysis . Obesity Surgery . 27 . 11 . 3021–3030 . November 2017 . 28889240 . 10.1007/s11695-017-2924-y . 4622165 .
  14. Poupon RE, Balkau B, Eschwège E, Poupon R . A multicenter, controlled trial of ursodiol for the treatment of primary biliary cirrhosis. UDCA-PBC Study Group . The New England Journal of Medicine . 324 . 22 . 1548–1554 . May 1991 . 1674105 . 10.1056/NEJM199105303242204 . free .
  15. Goulis J, Leandro G, Burroughs AK . Randomised controlled trials of ursodeoxycholic-acid therapy for primary biliary cirrhosis: a meta-analysis . Lancet . 354 . 9184 . 1053–1060 . September 1999 . 10509495 . 10.1016/S0140-6736(98)11293-X . 25562983 .
  16. Shi J, Wu C, Lin Y, Chen YX, Zhu L, Xie WF . 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 . 1529–1538 . July 2006 . 16863557 . 10.1111/j.1572-0241.2006.00634.x . 32076958 .
  17. Rudic JS, Poropat G, Krstic MN, Bjelakovic G, Gluud C . Ursodeoxycholic acid for primary biliary cirrhosis . The Cochrane Database of Systematic Reviews . 12 . 12 . CD000551 . December 2012 . 23235576 . 7045744 . 10.1002/14651858.CD000551.pub3 .
  18. Bowlus CL, Kenney JT, Rice G, Navarro R . Primary Biliary Cholangitis: Medical and Specialty Pharmacy Management Update . Journal of Managed Care & Specialty Pharmacy . 22 . 10-a-s Suppl . S3–S15 . October 2016 . 27700211 . 10.18553/jmcp.2016.22.10-a-s.s3 . 10408407 . free .
  19. Poropat G, Giljaca V, Stimac D, Gluud C . Bile acids for primary sclerosing cholangitis . The Cochrane Database of Systematic Reviews . 2011 . 1 . CD003626 . January 2011 . 21249655 . 7163275 . 10.1002/14651858.CD003626.pub2 .
  20. WHO Drug Information . 26 . 1 . 2012 . Ursodeoxycholic acid: serious hepatic events .
  21. 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 . High-dose ursodeoxycholic acid for the treatment of primary sclerosing cholangitis . Hepatology . 50 . 3 . 808–814 . September 2009 . 19585548 . 2758780 . 10.1002/hep.23082 .
  22. Walker KF, Chappell LC, Hague WM, Middleton P, Thornton JG . Pharmacological interventions for treating intrahepatic cholestasis of pregnancy . The Cochrane Database of Systematic Reviews . 2020 . 7 . CD000493 . July 2020 . 32716060 . 7389072 . 10.1002/14651858.CD000493.pub3 .
  23. Chappell LC, Bell JL, Smith A, Linsell L, Juszczak E, Dixon PH, Chambers J, Hunter R, Dorling J, Williamson C, Thornton JG . Ursodeoxycholic acid versus placebo in women with intrahepatic cholestasis of pregnancy (PITCHES): a randomised controlled trial . Lancet . 394 . 10201 . 849–860 . September 2019 . 31378395 . 6739598 . 10.1016/S0140-6736(19)31270-X .
  24. Kotb MA . Review of historical cohort: ursodeoxycholic acid in extrahepatic biliary atresia . Journal of Pediatric Surgery . 43 . 7 . 1321–1327 . July 2008 . 18639689 . 10.1016/j.jpedsurg.2007.11.043 .
  25. Book: Paediatric Formulary Committee . British National Formulary for Children 2008 . Pharmaceutical Press . London . 2008 . 91 . 978-0-85369-780-0.
  26. Web site: Urso package insert. . Birmingham, AL . Axcan Pharma U.S. . January 2000 . 25 April 2009 . 17 October 2006 . https://web.archive.org/web/20061017072157/http://www.axcan.com/pdf/urso_patient_brochure.pdf . dead .
  27. Kotb MA, Mosallam D, Basanti CW, El Sorogy ST, Badr AM, Abd El Baky HE, Draz IH . Ursodeoxycholic acid use is associated with significant risk of morbidity and mortality in infants with cholestasis: A strobe compliant study . Medicine . 99 . 7 . e18730 . February 2020 . 32049781 . 7035015 . 10.1097/MD.0000000000018730 .
  28. McCabe ME, Dilly CK . New Causes for the Old Problem of Bile Reflux Gastritis . Clinical Gastroenterology and Hepatology . 16 . 9 . 1389–1392 . September 2018 . 29505908 . 10.1016/j.cgh.2018.02.034 . free . 3748071 . 1805/15771 .
  29. Cheng K, Ashby D, Smyth RL . Ursodeoxycholic acid for cystic fibrosis-related liver disease . The Cochrane Database of Systematic Reviews . 9 . 9 . CD000222 . September 2017 . 28891588 . 6483662 . 10.1002/14651858.CD000222.pub4 . Cochrane Cystic Fibrosis and Genetic Disorders Group .
  30. Hempfling W, Dilger K, Beuers U . Systematic review: ursodeoxycholic acid--adverse effects and drug interactions . Alimentary Pharmacology & Therapeutics . 18 . 10 . 963–972 . November 2003 . 14616161 . 10.1046/j.1365-2036.2003.01792.x . 25738560 . free .
  31. Lleo A, Wang GQ, Gershwin ME, Hirschfield GM . Primary biliary cholangitis . Lancet . 396 . 10266 . 1915–1926 . December 2020 . 33308474 . 10.1016/S0140-6736(20)31607-X . 228086916 .
  32. Tint GS, Salen G, Shefer S . Effect of ursodeoxycholic acid and chenodeoxycholic acid on cholesterol and bile acid metabolism . Gastroenterology . 91 . 4 . 1007–1018 . October 1986 . 3527851 . 10.1016/0016-5085(86)90708-0 . free .
  33. Paumgartner G, Beuers U . Ursodeoxycholic acid in cholestatic liver disease: mechanisms of action and therapeutic use revisited . Hepatology . 36 . 3 . 525–531 . September 2002 . 12198643 . 10.1053/jhep.2002.36088 . 28282761 . free .
  34. Material Safety Data Sheet on Ursodiol MSDS. https://fscimage.fishersci.com/msds/70916.htm
  35. 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 . Ursodeoxycholic acid and lithocholic acid exert anti-inflammatory actions in the colon . American Journal of Physiology. Gastrointestinal and Liver Physiology . 312 . 6 . G550–G558 . June 2017 . 28360029 . 10.1152/ajpgi.00256.2016 . free .
  36. Lajczak NK, Saint-Criq V, O'Dwyer AM, Perino A, Adorini L, Schoonjans K, Keely SJ . 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 . September 2017 . 28487283 . 10.1096/fj.201601365R . 46877147 . free.
  37. Mroz MS, Lajczak NK, Goggins BJ, Keely S, Keely SJ . 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 . March 2018 . 29351391 . 10.1152/ajpgi.00435.2016 . 3767047 .
  38. O'Dwyer AM, Lajczak NK, Keyes JA, Ward JB, Greene CM, Keely SJ . Ursodeoxycholic acid inhibits TNFα-induced IL-8 release from monocytes . American Journal of Physiology. Gastrointestinal and Liver Physiology . 311 . 2 . G334–G341 . August 2016 . 27340129 . 10.1152/ajpgi.00406.2015 . free .
  39. Akare S, Jean-Louis S, Chen W, Wood DJ, Powell AA, Martinez JD . Ursodeoxycholic acid modulates histone acetylation and induces differentiation and senescence . International Journal of Cancer . 119 . 12 . 2958–2969 . December 2006 . 17019713 . 10.1002/ijc.22231 . 21187798 .
  40. Devlin AS, Fischbach MA . A biosynthetic pathway for a prominent class of microbiota-derived bile acids . Nature Chemical Biology . 11 . 9 . 685–690 . September 2015 . 26192599 . 4543561 . 10.1038/nchembio.1864 .
  41. Tonin F, Arends IW . Latest development in the synthesis of ursodeoxycholic acid (UDCA): a critical review . Beilstein Journal of Organic Chemistry . 14 . 470–483 . 2018 . 29520309 . 5827811 . 10.3762/bjoc.14.33 . free .
  42. Feng Y, Siu K, Wang N, Ng KM, Tsao SW, Nagamatsu T, Tong Y . Bear bile: dilemma of traditional medicinal use and animal protection . Journal of Ethnobiology and Ethnomedicine . 5 . 1 . 2 . January 2009 . 19138420 . 2630947 . 10.1186/1746-4269-5-2 . free .
  43. Arakawa T, Kagaya A, Inaba Y . Ursodesoxycholic acid as in accelerator for riboflavin phosphorylation in children with nutritional dystrophy . The Journal of Vitaminology . 3 . 3 . 165–167 . September 1957 . 13476545 . 10.5925/jnsv1954.3.165 . free .
  44. Web site: Actigall: FDA-Approved Drugs . U.S. Food and Drug Administration (FDA) . 29 April 2020.
  45. Web site: Actigall Orphan Drug Designation and Approval . U.S. Food and Drug Administration (FDA) . 29 April 2020.

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