関: ursodeoxycholic acid

同: Actigall

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2014/04/05 09:18:15」(JST)

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Ursodeoxycholic acid (INN, BAN and AAN), also known as ursodiol (USAN) and the abbreviation UDCA, is one of the secondary bile acids, which are metabolic byproducts of intestinal bacteria.

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]

Medical uses

A Cochrane review looking at primary biliary cirrhosis found that although ursodeoxycholic acid showed a reduction in liver biochemistry, jaundice, and ascites, it did not decrease mortality or liver transplantation.^[4] Ursodiol is the only FDA approved drug to treat primary biliary cirrhosis.^[5]

Ursodiol may be used for biliary stasis in pregnant women to relieve the symptoms of itching and decrease bile absorption.^[6]

In absence of biochemical response to ursodeoxycholic acid, its use is associated with an incidence of 20% hepatocellular carcinoma in those 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 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). The risk was 2.1 times greater for death,transplantation, or minimal listing criteria in patients on ursodeoxycholic acid than for those on placebo. Serious adverse events, were more common in the ursodeoxycholic acid group than the placebo group.^[11]

Mechanism of action

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.

Trade names

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

Production

The drug is generally not derived from animals.^{[citation needed]} However, it is believed up to 10,000^[12] bile bears are kept on farms in China, Vietnam and South Korea for the purpose of harvesting ursodeoxycholic acid.^[12] Ursodeoxycholic acid is found in large quantities in bear bile.^[13]

References

^ 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.
^ 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.
^ Material Safety Data Sheet on Ursodiol MSDS. https://fscimage.fishersci.com/msds/70916.htm
^ 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.
^ 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.
^ Mayo Clinic Staff. "Cholestasis of pregnancy: Treatment and Drugs". Mayo Clinic.
^ 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.
^ 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.
^ Paediatric Formulary Committee (2008). British National Formulary for Children 2008. London: Pharmaceutical Press. p. 91. ISBN 0-85369-780-9.
^ Urso package insert. Birmingham, AL: Axcan Pharma U.S.; 2000 Jan.http://www.axcan.com/pdf/urso_patient_brochure.pdf
^ 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.
^ ^a ^b Michael Bristow (29 February 2012). "China bear bile farms stir anger among campaigners". BBC News.
^ 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

UpToDate Contents

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1. 嚢胞性線維症：肝胆道系疾患 cystic fibrosis hepatobiliary disease
2. 原発性胆汁性肝硬変の治療の概要 overview of the treatment of primary biliary cirrhosis
3. 原発性胆汁性肝硬変治療用ウルソデオキシコール酸の臨床試験 trials of ursodeoxycholic acid for the treatment of primary biliary cirrhosis
4. 妊娠性肝内胆汁うっ滞 intrahepatic cholestasis of pregnancy
5. 造血細胞移植後の肝類洞閉塞症候群の治療および予防 treatment and prevention of hepatic sinusoidal obstruction syndrome following hematopoietic cell transplantation

English Journal

A novel high-pressure precipitation tandem homogenization technology for drug nanocrystals production - a case study with ursodeoxycholic acid.

Li Y, Wang Y, Yue PF, Hu PY, Wu ZF, Yang M, Yuan HL.Author information Key Lab of Modern Preparation of TCM, Ministry of Education, Jiangxi University of Traditional Chinese Medicine , Nanchang , China and.AbstractAbstract To overcome the limitations of the conventional particle size reduction technologies, a novel combinative particle size reduction method for the effective production of homogeneous nanosuspensions was investigated. Ursodeoxycholic acid, a poorly soluble drug representative, was tried to prepare nanosuspension by homogenization technology and high-pressure precipitation tandem homogenization technology. It was shown that the combinative approach could significantly improve the particle size reduction effectiveness over conventional homogenization approach. The Box-Behnken design analysis for process optimization revealed that the acceptable UDCA-NS was obtained wherein the optimal values of A, B, C and D were 10%, 500 bar, 0.125 and 600 bar, respectively. SEM results demonstrated that no significant aggregation or crystals growth could be observed in the freeze-dried UDCA nanocrystals. The DSC and XRD results showed that UDCA remained in a crystalline state. Dissolution velocities of the freeze-dried UDCA-NS powder were distinctly superior compared to those of the crude powder and physical mixture. The high-pressure precipitation tandem homogenization technology can be a good choice for nanosuspension preparation of poorly soluble UDCA, due to high efficiency of particle size reduction.
Pharmaceutical development and technology.Pharm Dev Technol.2014 Sep;19(6):662-70. doi: 10.3109/10837450.2013.819015. Epub 2013 Jul 22.
Abstract To overcome the limitations of the conventional particle size reduction technologies, a novel combinative particle size reduction method for the effective production of homogeneous nanosuspensions was investigated. Ursodeoxycholic acid, a poorly soluble drug representative, was tried to pre
PMID 23869484

Combination of submicroemulsion and phospholipid complex for novel delivery of ursodeoxycholic acid.

Ma YQ, Li G, Xu JH, Zhang J, Zhang ZZ, Xiao HY, Li XF.Author information Department of Pharmaceutics, the 94th Hospital of PLA , Nanchang , China.AbstractAbstract The objective of this study was to prepare and characterize ursodeoxycholic acid submicron emulsion (UA-SME) loaded with ursodeoxycholic acid phytosomes (UA-PS) and optimize the process variables. A screening experiment with response surface methodology with Box-Behnken design (BBD) was used to optimize the process parameters of UA-SME. The blood concentrations of UA after oral administration of UA-SME and UA coarse drug were assayed. The optimum process conditions were finally obtained by using a desirability function. It was found that stirring velocity, homogenization pressure and homogenization cycles were the most important variables that affected the particles size, polydispersity index and entrapment efficiency of UA-SME. Results showed that the optimum stirring velocity, homogenization pressure and cycles were 16 000 rpm, 60 MPa and 10 cycles, respectively. The mean diameter, polydispersity index and entrapment efficiency of UA-SME were 251.9 nm, 0.241 and 74.36%, respectively. Pharmacokinetic parameters of UA and UA-SME in rats were Tmax 2.215 and 1.489 h, Cmax 0.0364 and 0.1562 μg/mL, AUC0-∞ 3.682 and 13.756 μg h/mL, respectively. The bioavailability of UA in rats was significantly different (p < 0.05) after oral administration of UA-SME compared to those of UA coarse drug. This was due to improvement of the hydrophilicity and lipophilic property of UA-SME.
Pharmaceutical development and technology.Pharm Dev Technol.2014 May;19(3):363-72. doi: 10.3109/10837450.2013.788517. Epub 2013 May 1.
Abstract The objective of this study was to prepare and characterize ursodeoxycholic acid submicron emulsion (UA-SME) loaded with ursodeoxycholic acid phytosomes (UA-PS) and optimize the process variables. A screening experiment with response surface methodology with Box-Behnken design (BBD) was use
PMID 23634754

Review article: controversies in the management of primary biliary cirrhosis and primary sclerosing cholangitis.

Karlsen TH, Vesterhus M, Boberg KM.Author information Norwegian PSC Research Center, Division of Cancer Medicine, Surgery and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway; Department of Clinical Medicine, University of Bergen, Bergen, Norway.AbstractBACKGROUND: Despite considerable advances over the last two decades in the molecular understanding of cholestasis and cholestatic liver disease, little improvement has been made in diagnostic tools and therapeutic strategies.
Alimentary pharmacology & therapeutics.Aliment Pharmacol Ther.2014 Feb;39(3):282-301. doi: 10.1111/apt.12581. Epub 2013 Dec 29.
BACKGROUND: Despite considerable advances over the last two decades in the molecular understanding of cholestasis and cholestatic liver disease, little improvement has been made in diagnostic tools and therapeutic strategies.AIMS: To critically review controversial aspects of the scientific basis fo
PMID 24372568

Japanese Journal

A randomized controlled trial of colchicine plus ursodiol versus methotrexate plus ursodiol in primary biliary cirrhosis : ten-year results

Hepatology 39, 915-923, 2004
NAID 30015127681

Primary biliary cirrhosis : incidence and predictive factors of cirrhosis development in ursodiol-treated patients

Gastroenteenterology 122, 652-658, 2002
NAID 30023017178

Ursodiol use is associated with lower prevalence of colonic neoplasia in patients with ulcerative colitis and primary sclerosing cholangitis

Ann Intern Med 134, 89-95, 2001
NAID 10010855466

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「ウルソジオール」

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.	B3 (AU) B (US)
Legal status	Prescription Only (S4) (AU) ℞-only (CA) POM (UK) ℞-only (US)
Routes	oral
Identifiers
CAS number	128-13-2
ATC code	A05AA02
PubChem	CID 31401
DrugBank	DB01586
ChemSpider	29131
UNII	724L30Y2QR
KEGG	D00734
ChEBI	CHEBI:9907
ChEMBL	CHEMBL1551
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 ; Key:RUDATBOHQWOJDD-UZVSRGJWSA-N ;
Physical data
Melt. point	203 °C (397 °F)
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英: ursodiol
関: ウルソデオキシコール酸

[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.

[pmid19417220-2] 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] 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.

[5] 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.

[6] Mayo Clinic Staff. "Cholestasis of pregnancy: Treatment and Drugs". Mayo Clinic.

[pmid21389798-7] 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.

[BBC-12] Michael Bristow (29 February 2012). "China bear bile farms stir anger among campaigners". BBC News.

[13] 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

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ursodiol