Ursodeoxycholic acid

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Ursodeoxycholic acid
Ursodeoxycholic acid ball-and-stick.png
Clinical data
Trade names Actigall, Urso, others
Other namesUrsodiol
AHFS/Drugs.com Monograph
MedlinePlus a699047
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 InfoCard 100.004.437 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C24H40O4
Molar mass 392.580 g·mol−1
3D model (JSmol)
Melting point 203 °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 Yes check.svgY
  • Key:RUDATBOHQWOJDD-UZVSRGJWSA-N Yes check.svgY
   (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.

Contents

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.[ medical citation needed ]

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. [40]

Biosynthesis

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

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

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.[ citation needed ]

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. [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]

Related Research Articles

<span class="mw-page-title-main">Bile</span> Dark greenish-brown fluid aiding in the digestion of fats

Bile, or gall, is a yellow-green fluid produced by the liver of most vertebrates that aids the digestion of lipids in the small intestine. In humans, bile is primarily composed of water, produced continuously by the liver, and stored and concentrated in the gallbladder. After a human eats, this stored bile is discharged into the first section of their small intestine.

<span class="mw-page-title-main">Gallstone</span> Disease where stones form in the gallbladder

A gallstone is a stone formed within the gallbladder from precipitated bile components. The term cholelithiasis may refer to the presence of gallstones or to any disease caused by gallstones, and choledocholithiasis refers to the presence of migrated gallstones within bile ducts.

<span class="mw-page-title-main">Primary biliary cholangitis</span> Autoimmune disease of the liver

Primary biliary cholangitis (PBC), previously known as primary biliary cirrhosis, is an autoimmune disease of the liver. It results from a slow, progressive destruction of the small bile ducts of the liver, causing bile and other toxins to build up in the liver, a condition called cholestasis. Further slow damage to the liver tissue can lead to scarring, fibrosis, and eventually cirrhosis.

<span class="mw-page-title-main">Endoscopic retrograde cholangiopancreatography</span> Use of endoscopy and fluoroscopy to treat and diagnose digestive issues.

Endoscopic retrograde cholangiopancreatography (ERCP) is a technique that combines the use of endoscopy and fluoroscopy to diagnose and treat certain problems of the biliary or pancreatic ductal systems. It is primarily performed by highly skilled and specialty trained gastroenterologists. Through the endoscope, the physician can see the inside of the stomach and duodenum, and inject a contrast medium into the ducts in the biliary tree and pancreas so they can be seen on radiographs.

<span class="mw-page-title-main">Primary sclerosing cholangitis</span> Medical condition

Primary sclerosing cholangitis (PSC) is a long-term progressive disease of the liver and gallbladder characterized by inflammation and scarring of the bile ducts, which normally allow bile to drain from the gallbladder. Affected individuals may have no symptoms or may experience signs and symptoms of liver disease, such as yellow discoloration of the skin and eyes, itching, and abdominal pain.

<span class="mw-page-title-main">Liver disease</span> Medical condition

Liver disease, or hepatic disease, is any of many diseases of the liver. If long-lasting it is termed chronic liver disease. Although the diseases differ in detail, liver diseases often have features in common.

<span class="mw-page-title-main">Cholangiocarcinoma</span> Bile duct adenocarcinoma

Cholangiocarcinoma, also known as bile duct cancer, is a type of cancer that forms in the bile ducts. Symptoms of cholangiocarcinoma may include abdominal pain, yellowish skin, weight loss, generalized itching, and fever. Light colored stool or dark urine may also occur. Other biliary tract cancers include gallbladder cancer and cancer of the ampulla of Vater.

<span class="mw-page-title-main">Cholestasis</span> Medical condition

Cholestasis is a condition where the flow of bile from the liver to the duodenum is impaired. The two basic distinctions are:

<span class="mw-page-title-main">Chenodeoxycholic acid</span> One of the main bile acids

Chenodeoxycholic acid is a bile acid. Salts of this carboxylic acid are called chenodeoxycholates. Chenodeoxycholic acid is one of the main bile acids. It was first isolated from the bile of the domestic goose, which gives it the "cheno" portion of its name.

<span class="mw-page-title-main">Bile acid</span> Steroid acid found predominantly in the bile of mammals and other vertebrates

Bile acids are steroid acids found predominantly in the bile of mammals and other vertebrates. Diverse bile acids are synthesized in the liver. Bile acids are conjugated with taurine or glycine residues to give anions called bile salts.

Progressive familial intrahepatic cholestasis (PFIC) is a group of familial cholestatic conditions caused by defects in biliary epithelial transporters. The clinical presentation usually occurs first in childhood with progressive cholestasis. This usually leads to failure to thrive, cirrhosis, and the need for liver transplantation.

<span class="mw-page-title-main">Biliary tract</span> Organ system

The biliary tract refers to the liver, gallbladder and bile ducts, and how they work together to make, store and secrete bile. Bile consists of water, electrolytes, bile acids, cholesterol, phospholipids and conjugated bilirubin. Some components are synthesized by hepatocytes ; the rest are extracted from the blood by the liver.

<span class="mw-page-title-main">Gallbladder disease</span> Medical condition

Gallbladder diseases are diseases involving the gallbladder and is closely linked to biliary disease, with the most common cause being gallstones (cholelithiasis).

<span class="mw-page-title-main">Hyodeoxycholic acid</span> Chemical compound

Hyodeoxycholic acid, also known as 3α,6α-Dihydroxy-5β-cholan-24-oic acid or HDCA, is a secondary bile acid, one of the metabolic byproducts of intestinal bacteria. It differs from deoxycholic acid in that the 6α-hydroxyl is in the 12 position in the former. The 6α-hydroxyl group makes HDCA a hydrophilic acid, a property it shares with hyocholic acid. HDCA is present in mammalian species in different proportions. It is the main acid constituent of hog bile, and for this reason it was used industrially as precursor for steroid synthesis before total synthesis became practical.

Secondary sclerosing cholangitis (SSC) is a chronic cholestatic liver disease. SSC is a sclerosing cholangitis with a known cause. Alternatively, if no cause can be identified, then primary sclerosing cholangitis is diagnosed. SSC is an aggressive and rare disease with complex and multiple causes. It is characterized by inflammation, fibrosis, destruction of the biliary tree and biliary cirrhosis. It can be treated with minor interventions such as continued antibiotic use and monitoring, or in more serious cases, laparoscopic surgery intervention, and possibly a liver transplant.

Vanishing bile duct syndrome is a loose collection of diseases which leads to the injury to hepatic bile ducts and eventual ductopenia.

<span class="mw-page-title-main">Ursodoxicoltaurine</span> Chemical compound

Ursodoxicoltaurine is the international nonproprietary name (INN) for the pharmaceutical form of tauroursodeoxycholic acid (TUDCA). It is also known as taurursodiol. Tauroursodeoxycholic acid is a naturally occurring hydrophilic bile acid which is the taurine conjugated form of ursodeoxycholic acid (UDCA). Humans have only trace amounts of tauroursodeoxycholic acid but bears have large amounts of tauroursodeoxycholic acid and ursodeoxycholic acid in their bile.

<span class="mw-page-title-main">Obeticholic acid</span> Chemical compound

Obeticholic acid (OCA), sold under the brand name Ocaliva, is a semi-synthetic bile acid analogue which has the chemical structure 6α-ethyl-chenodeoxycholic acid. It is used as a medication used to treat primary biliary cholangitis. Intercept Pharmaceuticals Inc. hold the worldwide rights to develop OCA outside Japan and China, where it is licensed to Dainippon Sumitomo Pharma.

Intercept Pharmaceuticals, Inc. is an American biopharmaceutical company incorporated in 2002, focusing on the development of novel synthetic bile acid analogs to treat chronic liver diseases, such as primary biliary cirrhosis (PBC) now called primary biliary cholangitis, non-alcoholic fatty liver disease, cirrhosis, portal hypertension, primary sclerosing cholangitis and also the intestinal disorder, bile acid diarrhea.

References

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  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.
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  9. ↑ "2020 First Generic Drug Approvals". U.S. Food and Drug Administration (FDA). 23 February 2021. Retrieved 25 September 2021.
  10. ↑ "Ursodiol: FDA-Approved Drugs". U.S. Food and Drug Administration (FDA). Retrieved 25 September 2021.
  11. 1 2 Hofmann AF (September 1989). "Medical dissolution of gallstones by oral bile acid therapy". American Journal of Surgery. 158 (3): 198–204. doi:10.1016/0002-9610(89)90252-3. PMID   2672842.
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  17. ↑ 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 (12): CD000551. doi:10.1002/14651858.CD000551.pub3. PMC   7045744 . PMID   23235576.
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  34. ↑ Material Safety Data Sheet on Ursodiol MSDS. https://fscimage.fishersci.com/msds/70916.htm
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  41. ↑ Devlin AS, Fischbach MA (September 2015). "A biosynthetic pathway for a prominent class of microbiota-derived bile acids". Nature Chemical Biology. 11 (9): 685–690. doi:10.1038/nchembio.1864. PMC   4543561 . PMID   26192599.
  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.
  45. ↑ "Actigall Orphan Drug Designation and Approval". U.S. Food and Drug Administration (FDA). Retrieved 29 April 2020.
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