Through FXR-mediated ACE2 modulation, ursodeoxycholic acid (10 μM; 24 h) lowers SARS-CoV-2 infection in different cell types and reduces ACE2 and SHP levels in primary airways and damaged organoids [4].

In C57BL/6J wild-type mice, ursodeoxycholic acid (50, 150, and 450 mg/kg; route); once daily for 21 days—causes weight loss [1]. In mice and hamsters, ursodeoxycholic acid (1% w/w or 416 mg/kg; port; 7 days) decreases ACE2 expression [4]. In hamsters, ursodeoxycholic acid (416 mg/kg; side wall; 7 days) is effective in reducing SARS-CoV-2 infection [4].

Animal/Disease Models: 5weeks old C57BL/6J WT mice (male and female) [1]
Doses: 50, 150 and 450 mg/kg dissolved in corn oil
Route of Administration: po (oral gavage); one time/day for 21 days
Experimental Results: Mice in the 50 mg/kg and 450 mg/kg groups continued to lose significant weight within a week. At the 50 mg/kg dose, this weight loss persisted throughout the experiment. At the 450 mg/kg dose, weight loss was initially noted during the first and third weeks of ursodiol administration. At the 150 mg/kg dose, there was no significant difference in body weight compared to untreated mice.

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Animal/Disease Models: FVB/N mice and Syrian golden hamsters [4]
Doses: 1% w/w for mice, 416 mg/kg for hamsters.
Route of Administration: feed or po (oral gavage), 7 days.
Experimental Results: ACE2 expression diminished.

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Animal/Disease Models: Syrian golden hamster, SARS-CoV-2 infection model [4]
Doses: 416 mg/kg
Route of Administration: po (oral gavage), 7 days
Experimental Results: n = 6 of 9 sentinel animals prevented SARS -Transmission of CoV-2 (33% infected vs. 67% uninfected).

Absorption, Distribution and Excretion
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.

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Metabolism / Metabolites
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.

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Biological Half-Life
The estimated half-life ranges from 3.5 to 5.8 days.

Hepatotoxicity
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).

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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Ursodiol is naturally present in human milk. Because of the low levels of ursodiol (ursodeoxycholic acid) 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 directly to newborns to safely and successfully treat prolonged 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.

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Protein Binding
Unconjugated ursodeoxycholic acid is at least 70% bound to plasma proteins in health individuals. There is no information regarding the protein binding of conjugated ursodeoxycholic acid.

[1]. Secondary bile acid ursodeoxycholic acid alters weight, the gut microbiota, and the bile acid pool in conventional mice. PLoS One. 2021;16(2):e0246161. Published 2021 Feb 18.

[2]. Influence of ursodeoxycholic acid on the mortality and malignancy associated with primary biliary cirrhosis: a population-based cohort study. Hepatology. 2007 Oct;46(4):1131-7.

[3]. Use of ursodeoxycholic acid in liver diseases. J Gastroenterol Hepatol. 2001 Jan;16(1):3-14.

[4]. FXR inhibition may protect from SARS-CoV-2 infection by reducing ACE2. Nature. 2022 Dec 5.

[5]. Specific Bile Acids Inhibit Hepatic Fatty Acid Uptake in Mice. Hepatology. 2012 Oct;56(4):1300-10.

Pharmacodynamics
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.

C24H40O4

392.5720

392.292

128-13-2

Ursodeoxycholic acid sodium;2898-95-5

31401

White to off-white solid powder

1.1±0.1 g/cm3

547.1±25.0 °C at 760 mmHg

203-206 ºC

298.8±19.7 °C

0.0±3.3 mmHg at 25°C

1.543

4.66

3

4

4

28

605

10

C[C@H](CCC(=O)O)[C@H]1CC[C@@H]2[C@@]1(CC[C@H]3[C@H]2[C@H](C[C@H]4[C@@]3(CC[C@H](C4)O)C)O)C

RUDATBOHQWOJDD-UZVSRGJWSA-N

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

(4R)-4-[(3R,5S,7S,8R,9S,10S,13R,14S,17R)-3,7-dihydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]pentanoic acid

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ≥ 100 mg/mL (~254.73 mM)
H2O : ~1 mg/mL (~2.55 mM)

Solubility in Formulation 1: ≥ 2.08 mg/mL (5.30 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.08 mg/mL (5.30 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.08 mg/mL (5.30 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)