ウルソデオキシコール酸

3

3.00

200-205

203 °C

200.0 Ų [M-H]- [CCS Type: DT; Buffer gas: N2; Ionization: ESI-; Dataset: Bile Acids]

208.98 Ų [M-H]- [CCS Type: DT; Method: stepped-field]

200.9 Ų [M-H]- [CCS Type: DT; Method: single field calibrated with ESI Low Concentration Tuning Mix (Agilent)]；198.7 Ų [M+Na]+ [CCS Type: DT; Method: single field calibrated with ESI Low Concentration Tuning Mix (Agilent)]

203.2 Ų [M+Na-H+HCOO]- [CCS Type: DT; Method: single field calibrated]；198.3 Ų [M-H]- [CCS Type: DT; Method: single field calibrated]；199.4 Ų [M+Na-H+Cl]- [CCS Type: DT; Method: single field calibrated]；186.8 Ų [M+H-2H2O]+ [CCS Type: DT; Method: single field calibrated]；200.2 Ų [M+HCOO]- [CCS Type: DT; Method: single field calibrated]；205.7 Ų [M+K-H+HCOO]- [CCS Type: DT; Method: single field calibrated]

198.86 Ų [M+K]+ [CCS Type: TW; Method: calibrated with polyalanine and drug standards]；193.71 Ų [M+H]+ [CCS Type: TW; Method: calibrated with polyalanine and drug standards]；196.65 Ų [M+Na]+ [CCS Type: TW; Method: calibrated with polyalanine and drug standards]

This chemical does not meet GHS hazard criteria for 4.5% (2 of 44) of reports.

Warning

H315 (95.5%): Causes skin irritation [Warning Skin corrosion/irritation]；H319 (95.5%): Causes serious eye irritation [Warning Serious eye damage/eye irritation]

P264, P264+P265, P280, P302+P352, P305+P351+P338, P321, P332+P317, P337+P317, and P362+P364 (click each P-code to see the statement)

Aggregated GHS information provided per 44 reports by companies from 4 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.；Reported as not meeting GHS hazard criteria per 2 of 44 reports by companies.；There are 3 notifications provided by 42 of 44 reports by companies with hazard statement code(s).；Information may vary between notifications depending on impurities, additives, and other factors. The percentage value in parenthesis indicates the notified classification ratio from companies that provide hazard codes. Only hazard codes with percentage values above 10% are shown. For more detailed information, please visit ECHA C&L website.

Status: Active Update: 06-03-2023 https://echa.europa.eu/registration-dossier/-/registered-dossier/5699；Status: Active Update: 06-09-2018 https://echa.europa.eu/registration-dossier/-/registered-dossier/27118

Ursodeoxycholic acid: Does not have an individual approval but may be used as a component in a product covered by a group standard. It is not approved for use as a chemical in its own right.

n multiple clinical trials in a variety of conditions, ursodiol has not been found to cause increases in serum enzyme elevations, worsening of underlying liver disease or clinically apparent liver injury. Nevertheless, there have been rare reports of clinical decompensation in patients with advanced liver disease and cirrhosis started on ursodiol, but the reason for such reactions is not known. In at least one instance, there was recurrence of jaundice on restarting ursodiol. Thus, ursodiol has beneficial effects on several forms of liver disease and has not been convincingly linked to cases of clinically apparent acute liver injury in patients without cirrhosis. There is some concern that ursodiol may be harmful in patients with advanced liver disease (Childs class B and C) and such patients probably should not receive ursodiol.；Likelihood score: D (possible rare cause of acute decompensation of preexisting liver disease).

UDCA is a mostly well-tolerated drug. In most clinical trials, diarrhea was the most frequent adverse event observed during UDCA treatment in patients with gallstone disease, with a reported incidence of 2 to 9%. The mechanism behind this side effect is unclear. However, researchers have proposed that bacterial conversion of UDCA to chenodeoxycholic acid, which serves as a potent secretory substance, could significantly contribute to this side effect. In patients with primary biliary cirrhosis, right upper quadrant abdominal pain was the most commonly reported side effect. Reports also exist of skin reactions in those with primary biliary cirrhosis. The most common dermatological manifestation was an exacerbation of pruritus, even though UDCA has demonstrated effectiveness in relieving pruritus in patients with PBC in other trials.

UDCA has been shown to have potentially toxic molecular properties. UDCA breaks down into toxic lithocholic acid. After being absorbed in the small intestine, UDCA undergoes hepatic conjugation. Beyond conjugation, UDCA does not experience further breakdown by the liver or intestinal mucosa. It becomes oxidized or reduced, yielding either 7-keto-lithocholic acid or lithocholic acid. Litcholic acid can be toxic to liver cells and even cause liver failure in those with compromised sulfation. It also leads to segmental bile duct injury, hepatocyte failure, and death.

Drug Induced Liver Injury Rank (DILIrank 2.0)

Ursodiol

Ambiguous-DILI-concern

0

Warnings & precautions

DOI:10.1016/j.drudis.2016.02.015

◉ Summary of Use during Lactation；Ursodiol (ursodeoxycholic acid) is naturally present in human milk. Because of the low levels of ursodiol in breastmilk after exogenous administration, amounts ingested by the infant are small and are not expected to cause any adverse effects in breastfed infants. Ursodiol has been given safely directly to newborns treat neonatal jaundice. No special precautions are required.；◉ Effects in Breastfed Infants；One breastfed (extent not stated) infant developed normally over the first 6 months of life during maternal ursodiol therapy of 750 to 1000 mg daily.；Seven women who were taking ursodiol 14 mg/kg daily near term and postpartum. They reported no adverse reactions in their breastfed infants during the early postpartum period.；A mother receiving oral ursodiol 250 mg 3 times daily for primary biliary cirrhosis reportedly breastfed her infant normally, although the extent and duration of breastfeeding was not stated.；A woman with primary biliary cirrhosis developed severe pruritus and elevated serum bile acids 3 weeks postpartum. Ursodiol was started at a dose of 500 mg (7.5 mg/kg) daily, increasing to 1500 mg (25 mg/kg) daily over the next 8 weeks. Psychomotor development of her breastfed (extent not stated) infant was normal, and no apparent side effects were observed in the infant.；A retrospective review of the medical records of pregnant patients at a hospital in Ankara, Türkiye who had a diagnosis of primary biliary cirrhosis found 8 patients who took ursodiol postpartum in doses of 13–15 mg/kg daily. “Most” of the patients breastfed their infants (extent not stated). No infant side effects were reported.；A woman was breastfeeding her 8-day-old preterm infant 10 times daily for about 15 minutes each time. The infant was born by cesarean section at 34 weeks of gestation with a weight of 3600 grams. She was diagnosed with cholestasis, type 1 diabetes, and hypothyroidism. She was treated with ursodiol 500 mg daily, insulin levemir and aspart, and levothyroxine. She was also taking cefuroxime, flurbiprofen, a combination of acetaminophen, propyphenazone, and caffeine. The mother took the ursodiol for a total of 12 days, cefuroxime and the analgesic combination for 10 days and flurbiprofen for 15 days. No adverse effects were noticed during the period of ursodiol treatment.；Twenty nursing mothers were taking ursodiol for cholestasis in daily dosages of 500 to 1500 mg or 13 to 15 mg/kg, depending on the condition. Ursodiol was discontinued 3 days postpartum. No apparent side effects were observed in any newborn infant based on standard clinical examination during early postnatal period, and no deterioration in postnatal development was observed during routine 1-year follow-up on routine pediatric examinations.；◉ Effects on Lactation and Breastmilk；Relevant published information was not found as of the revision date.

Status: Active Update: 06-03-2023 https://echa.europa.eu/registration-dossier/-/registered-dossier/5699；Status: Active Update: 06-09-2018 https://echa.europa.eu/registration-dossier/-/registered-dossier/27118

Ursodeoxycholic acid: Does not have an individual approval but may be used as a component in a product covered by a group standard. It is not approved for use as a chemical in its own right.

A05AA02

A - Alimentary tract and metabolism；A05 - Bile and liver therapy；A05A - Bile therapy；A05AA - Bile acids and derivatives；A05AA02 - Ursodeoxycholic acid

QA - Alimentary tract and metabolism；QA05 - Bile and liver therapy；QA05A - Bile therapy；QA05AA - Bile acids and derivatives；QA05AA02 - Ursodeoxycholic acid

Ursodeoxycholic acid (UDCA) is a secondary bile acid with cytoprotectant, immunomodulating, and choleretic effects. It reduces the cholesterol fraction of biliary lipids. UDCA inhibits the absorption of cholesterol in the intestine and the secretion of cholesterol into bile, decreasing biliary cholesterol saturation. UDCA increases bile acid flow and promotes the secretion of bile acids.

Endogenous hydrophobic bile acids such as deoxycholic acid and chenodeoxycholic acid can exert hepatotoxic effects. Ursodeoxycholic acid is a hydrophilic bile acid that mediates its biological effects via several mechanisms. Ursodeoxycholic acid (UDCA) protects hepatocytes and cholangiocytes from bile acid-induced damage, such as reactive oxygen species (ROS)-induced inflammation and mitochondrial dysfunction. UDCA was shown to reserve hepatocyte cell structures and stimulate anti-apoptotic pathways. It was also shown to prevent the production of ROS by Kupffer cells and resident macrophages in the liver, thus attenuating oxidative stress in the liver. UDCA can also change the hydrophobicity index of the bile acid pool: following oral administration, UDCA forms a major fraction of the human bile acid pool and competitively displaces the hydrophobic or more toxic bile acids. It increases the absorption of hydrophilic bile acids. There are several proposed mechanisms of choleretic actions of UDCA: UDCA increases intracellular calcium levels, stimulating transport proteins and vesicular exocytosis in cholestatic hepatocytes. UDCA may also upregulate the expression of membrane transport proteins like the chloride-bicarbonate anion exchanger (AE2), which is involved in biliary secretion and is often observed to be defective in primary biliary cholangitis. In rats, UDCA reduced hepatic expression of major histocompatibility complex (MHC) class I antigens, suggesting immunomodulating effects. UDCA acts as a partial agonist at the bile acid receptor, also known as the farnesoid X receptor (FXR), and has negligible effects on cholesterol and lipid synthesis.

Upon administration, ursodeoxycholic acid (UDCA) enters the portal vein and into the liver, where it undergoes conjugation with glycine or taurine. UDCA is also decreased into bile. Glycine or taurine conjugates are absorbed in the small intestine via passive and active mechanisms. The conjugates can also be deconjugated in the ileum by intestinal enzymes, leading to the formation of free UDCA that can be reabsorbed and re-conjugated in the liver. Nonabsorbed UDCA passes into the colon, where it undergoes 7-dehydroxylation by intestinal bacteria to lithocholic acid. Some UDCA is epimerized to [chenodeoxycholic acid] via a 7-oxo intermediate. Chenodeoxycholic acid also undergoes 7-dehydroxylation to form lithocholic acid. These metabolites are poorly soluble and excreted in the feces. A small portion of lithocholic acid is reabsorbed, conjugated in the liver with glycine or taurine, and sulfated at the 3 position. The resulting sulfated lithocholic acid conjugates are excreted in bile and then lost in feces.

724L30Y2QR

URSODIOL

Established Pharmacologic Class [EPC] - Bile Acid

Chemical Structure [CS] - Bile Acids and Salts

Ursodiol is a Bile Acid.

URSODIOL

Normally, endogenous ursodeoxycholic acid constitutes a minor fraction (about 5%) of the total human bile acid pool. Following oral administration, the majority of ursodiol is absorbed by passive diffusion, and its absorption is incomplete. Once absorbed, ursodiol undergoes hepatic extraction to about 50% in the absence of liver disease. As the severity of liver disease increases, the extent of extraction decreases. During chronic administration of ursodiol, it becomes a major biliary and plasma bile acid. At a chronic dose of 13 to 15 mg/kg/day, ursodiol constitutes 30-50% of biliary and plasma bile acids.

Ursodeoxycholic acid is excreted primarily in the feces. Renal elimination is a minor elimination pathway. With treatment, urinary excretion increases but remains less than 1% except in severe cholestatic liver disease.

The volume of distribution of ursodeoxycholic acid (UDCA) has not been determined; however, it is expected to be small since UDCA is mostly distributed in the bile in the gallbladder and small intestines.