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Ursodeoxycholic acid

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Ursodeoxycholic acid
Clinical data
Trade namesActigall, Urso, others
Other namesUrsodiol
AHFS/Drugs.comMonograph
MedlinePlusa699047
License data
Pregnancy
category
Routes of
administration		By mouth
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 mass392.580 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 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

[edit]

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

[edit]

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

[edit]

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

[edit]

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

[edit]

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

[edit]

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.[medical citation needed]

Adverse effects

[edit]

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

[edit]

Choleretic effects

[edit]

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

[edit]

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

[edit]

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

[edit]

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.[40]

Biosynthesis

[edit]

Among mammals, only bears (Ursidae; excluding giant pandas) produce UDCA at useful amounts[40] (>30%). It is produced in the bear liver, but the pathway remains unknown.[8]

Other vertebrates produce UDCA in much smaller amounts by gut bacteria. CDCA is oxidized into 7-oxo-CDCA then reduced into UDCA.[41]

Industrial production

[edit]

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%.[42]

Society and culture

[edit]

Names

[edit]

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.[citation needed]

History

[edit]

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.[40] 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]

References

[edit]
  1. ^ "Ursodiol, Heptiza 300/150 Use During Pregnancy". Drugs.com. 4 November 2019. Retrieved 20 February 2020.
  2. ^ "Prescription medicines: registration of new generic medicines and biosimilar medicines, 2017". Therapeutic Goods Administration (TGA). 21 June 2022. Retrieved 30 March 2024.
  3. ^ "Product information". Health Canada. 3 August 2000. Retrieved 3 March 2024.
  4. ^ "Details for: Ursodiol C". Health Canada. 25 October 2021. Retrieved 3 March 2024.
  5. ^ "Ursodeoxycholic acid 300mg Tablets - Summary of Product Characteristics (SmPC)". (emc). 10 July 2019. Retrieved 29 April 2020.
  6. ^ "Actigall- ursodiol capsule". DailyMed. Retrieved 25 September 2021.
  7. ^ "Urso 250- ursodiol tablet, film coated Urso Forte- ursodiol tablet, film coated". DailyMed. Retrieved 25 September 2021.
  8. ^ a b c Hagey LR, Crombie DL, Espinosa E, Carey MC, Igimi H, Hofmann AF (November 1993). "Ursodeoxycholic acid in the Ursidae: biliary bile acids of bears, pandas, and related carnivores". Journal of Lipid Research. 34 (11): 1911–1917. doi:10.1016/S0022-2275(20)35109-9. PMID 8263415.
  9. ^ "2020 First Generic Drug Approvals". U.S. Food and Drug Administration (FDA). 23 February 2021. Retrieved 25 September 2021.
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  34. ^ Material Safety Data Sheet on Ursodiol MSDS. https://fscimage.fishersci.com/msds/70916.htm
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  36. ^ Lajczak NK, Saint-Criq V, O'Dwyer AM, Perino A, Adorini L, Schoonjans K, et al. (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. S2CID 46877147.
  37. ^ 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. S2CID 3767047.
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  39. ^ 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): 2958–2969. doi:10.1002/ijc.22231. PMID 17019713. S2CID 21187798.
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  42. ^ Tonin F, Arends IW (2018). "Latest development in the synthesis of ursodeoxycholic acid (UDCA): a critical review". Beilstein Journal of Organic Chemistry. 14: 470–483. doi:10.3762/bjoc.14.33. PMC 5827811. PMID 29520309.
  43. ^ Arakawa T, Kagaya A, Inaba Y (September 1957). "Ursodesoxycholic acid as in accelerator for riboflavin phosphorylation in children with nutritional dystrophy". The Journal of Vitaminology. 3 (3): 165–167. doi:10.5925/jnsv1954.3.165. PMID 13476545.
  44. ^ "Actigall: FDA-Approved Drugs". U.S. Food and Drug Administration (FDA). Retrieved 29 April 2020.
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