Ursodiol

Ursodiol, also known as ursodeoxycholic acid and the abbreviation UDCA, is one of the secondary bile acids, which are metabolic byproducts of intestinal bacteria.

Ursodeoxycholic acid

Systematic (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
Clinical data
Trade names	Actigall
AHFS/Drugs.com	monograph
MedlinePlus	a699047
Licence data	US Daily Med:link
Pregnancy cat.	B (US)
Legal status	℞-only (US)
Routes	oral
Identifiers
CAS number	128-13-2 Y
ATC code	A05AA02
PubChem	CID 31401
DrugBank	DB01586
ChemSpider	29131 Y
UNII	724L30Y2QR Y
KEGG	D00734 Y
ChEBI	CHEBI:9907 Y
ChEMBL	CHEMBL1551 Y
Synonyms	ursodeoxycholic acid, Actigall, Ursosan, Urso, Urso Forte
Chemical data
Formula	C24H40O4
Mol. mass	392.56 g/mol
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
InChI 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 Y Key:RUDATBOHQWOJDD-UZVSRGJWSA-N Y
Physical data
Melt. point	203 °C (397 °F)
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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.

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]

As a pharmaceutical

Ursodeoxycholic acid can be chemically synthesized and is marketed under multiple trade names, including Actigall, BILIVER, Coric, Deursil, Egyurso, Udiliv, Urso, Urso Forte, Ursocol, Ursofalk, and Ursosan.

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

It is the only FDA approved drug to treat primary biliary cirrhosis.^[4]

Ursodiol may be used for biliary stasis in pregnant women to relieve the symptoms of itching and decrease bile absorption.^[5]

A Cochrane review to evaluate if ursodeoxycholic acid has any beneficial effect in primary biliary cirrhosis patients included 16 randomized clinical trials with a total of 1447 patients. The primary outcome measures were morbidity and mortality or liver transplantation. Although treatment with ursodeoxycholic acid showed a reduction in liver biochemistry, jaundice, and ascites, it did not decrease mortality or liver transplantation.^[6]

In absence of biochemical response to 13-15mg/kg/day ursodeoxycholic acid, its use is associated with an incidence of 20% hepatocellular carcinoma in patients with primary biliary cirrhosis in 15 years.^[7]

In children, its use is not licensed, as its safety and effectiveness are not established.^[8][9][10]

In double the recommended daily dose ursodeoxycholic acid reduces elevated liver enzyme levels in patients 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). After adjustment for baseline stratification characteristics, the risk was 2.1 times greater for death,transplantation, or minimal listing criteria in patients on ursodeoxycholic acid than for those on placebo (P = 0.038). Serious adverse events, were more common in the ursodeoxycholic acid group than the placebo group (63% versus 37% [P < 0.01])).^[11]

Research by the Imperial College London has produced promising results in the treatment of arrhythmia, both in patients who have suffered a heart attack and in foetuses, by using ursodiol to change the electrical properties of myofibroblast cells. Myofibroblasts disrupt the transmission of electrical signals controlling heart rhythm. ^[12]

Production

The drug is generally not derived from animals.^{[citation needed]} However, it is believed up to 10,000^[13] bile bears are kept on farms in China, Vietnam and South Korea for the purpose of harvesting ursodeoxycholic acid.^[13] Ursodeoxycholic acid is found in large quantities in bear bile.^[14]

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. Journal International Du 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. 
3. ↑ Material Safety Data Sheet on Ursodiol MSDS. https://fscimage.fishersci.com/msds/70916.htm
4. ↑ Jackson H, Solaymani-Dodaran M, Card TR, Aithal GP, Logan R, West J (October 2007). "Influence of ursodeoxycholic acid on the mortality and malignancy associated with primary biliary cirrhosis: a population-based cohort study". Hepatology 46 (4): 1131–7. doi:10.1002/hep.21795. PMID 17685473. 
5. ↑ Mayo Clinic Staff. "Cholestasis of pregnancy: Treatment and Drugs". Mayo Clinic. 
6. ↑ Gong Y, Huang ZB, Christensen E, Gluud C (2008). "Ursodeoxycholic acid for primary biliary cirrhosis". In Gong, Yan. Cochrane Database of Systematic Reviews (3): CD000551. doi:10.1002/14651858.CD000551.pub2. PMID 18677775. 
7. ↑ Kuiper EM, Hansen BE, Adang RP, van Nieuwkerk CM, Timmer R, Drenth JP, Spoelstra P, Brouwer HT, Kuyvenhoven JP, van Buuren HR (December 2010). "Relatively high risk for hepatocellular carcinoma in patients with primary biliary cirrhosis not responding to ursodeoxycholic acid". European Journal of Gastroenterology & Hepatology 22 (12): 1495–502. doi:10.1097/MEG.0b013e32834059e7. PMID 21389798. 
8. ↑ 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. 
9. ↑ Paediatric Formulary Committee (2008). British National Formulary for Children 2008. London: Pharmaceutical Press. p. 91. ISBN 0-85369-780-9. 
10. ↑ Urso package insert. Birmingham, AL: Axcan Pharma U.S.; 2000 Jan.http://www.axcan.com/pdf/urso_patient_brochure.pdf
11. ↑ 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. 
12. ↑ BBC News
13. ↑ 13.0 13.1 Michael Bristow (29 February 2012). "China bear bile farms stir anger among campaigners". BBC News. 
14. ↑ 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. J. Lipid Res. 1993 34:(11) 1911-1917. http://www.jlr.org/content/34/11/1911

External links

• Ursodeoxycholic acid information at MedlinePlus