Ursodeoxycholic Acid (DB01586): A Comprehensive Monograph on its Pharmacology, Clinical Efficacy, and Therapeutic Landscape

I. Introduction: A Naturally Derived Bile Acid in Modern Medicine

Historical Context and Overview

Ursodeoxycholic acid (UDCA), known pharmaceutically as ursodiol, is a secondary bile acid with a remarkable history that bridges ancient traditional medicine with modern molecular pharmacology. Its story begins not in a laboratory, but in the natural world, where it was first identified as a major constituent of the bile of bears from the genus Ursus, from which its name is derived.[1] For centuries, bear bile has been a staple in traditional Chinese medicine, where it was empirically used to "clear heat, relieve toxin, and clear away liver fire," presaging its contemporary applications in hepatobiliary disorders.[1] This long history of perceived therapeutic benefit laid the groundwork for scientific investigation, culminating in its successful chemical synthesis by Japanese scientists in 1955, a pivotal moment that enabled its widespread study and production.[1]

Chemically, UDCA is the 7β-epimer of chenodeoxycholic acid, a primary bile acid in humans.[1] In healthy individuals, UDCA is naturally present but constitutes only a minor fraction, typically less than 5%, of the total circulating bile acid pool.[2] Its key distinguishing feature is its relative hydrophilicity compared to the more common and potentially cytotoxic endogenous bile acids like cholic acid and chenodeoxycholic acid.[2] This fundamental physicochemical property is the cornerstone of its therapeutic action, rendering it less toxic and allowing it to safely modify the bile acid environment when administered exogenously.

Core Therapeutic Principles

In modern medicine, UDCA has been established as a cornerstone therapy for a select group of cholestatic liver diseases and as a non-surgical option for the medical dissolution of cholesterol-rich gallstones.[1] Its clinical utility is underpinned by a triad of pharmacological actions: cytoprotection (protecting liver cells), choleresis (stimulating bile flow), and immunomodulation.[6] The journey of UDCA into the Western pharmacopeia was formalized with its first approval by the U.S. Food and Drug Administration (FDA) in 1987 for the dissolution of gallstones, followed by its approval for the treatment of Primary Biliary Cholangitis (PBC) in 1996.[1] These approvals marked the successful translation of a compound from the realm of ethnopharmacology into a precisely synthesized, evidence-based pharmaceutical agent, demonstrating a valuable pathway for drug discovery. Today, UDCA remains a vital tool in the management of hepatobiliary disorders, and its well-understood mechanisms and favorable safety profile have spurred investigation into a surprisingly broad range of new therapeutic areas.

II. Physicochemical Properties and Pharmaceutical Formulations

Chemical Identification

A precise understanding of the chemical identity of Ursodeoxycholic acid is fundamental to its study and application. It is a small molecule classified as a dihydroxy bile acid and sterol lipid.[5]

• IUPAC Name: The systematic name for the compound is (3α,5β,7β)-3,7-dihydroxycholan-24-oic acid.[1] An alternative systematic name is (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.[1]
• Synonyms: The most common synonym and generic name is Ursodiol.[1] Other recognized synonyms include UDCA, Acide ursodesoxycholique, 5β-Cholanic Acid-3α,7β-diol, 3α,7β-Dihydroxy-5β-cholanic Acid, and NSC 683769.[1]
• Identifiers: The compound is uniquely identified across various chemical and drug databases by the following numbers:
• CAS Number: 128-13-2 [13]
• DrugBank ID: DB01586 [5]
• EC Number: 204-879-3 [19]
• PubChem Substance ID: 87577760 [15]
• Beilstein/REAXYS Number: 3219888 [18]
• Molecular Formula and Weight: The empirical formula for UDCA is C24​H40​O4​.[6] Its calculated average molecular weight is consistently reported as 392.57 g/mol or 392.58 g/mol, with a monoisotopic weight of 392.292659768 g/mol.[1]

Physical and Chemical Characteristics

The physical properties of UDCA dictate its formulation, handling, and aspects of its biological activity.

• Appearance: In its purified form, UDCA is a white to almost-white crystalline powder.[15] It is noted to have a bitter taste, a characteristic that can influence patient compliance, particularly with broken tablets.[20]
• Solubility: The solubility profile of UDCA is critical to its mechanism of action. It is practically insoluble in water (reported as 20 mg/L at 20°C) but is freely soluble in organic solvents like ethanol and methanol, and sparingly soluble in chloroform.[12] Its insolubility in aqueous media is a key factor in its unique ability to disperse cholesterol as liquid crystals, a mechanism central to gallstone dissolution.[20]
• Melting Point: The melting point is a consistent and reliable identifier, reported within a narrow range of 200°C to 205°C, with many sources citing 203-204°C.[1]
• Other Properties: Additional defining characteristics include its specific optical rotation, [α]20/D, which is between +59.0° and +62.0° (c=4, EtOH), and its acid dissociation constant (pKa) of approximately 5.04.[15]

Pharmaceutical Formulations and Brand Names

UDCA is marketed globally under various brand names and is available in distinct oral formulations, often tailored to specific indications.

• Dosage Forms: The medication is available for oral administration as both capsules and tablets.[14] This distinction is clinically relevant, as capsules are often indicated for gallstone-related conditions, while tablets are typically prescribed for Primary Biliary Cholangitis.
• Strengths:
• Capsules: Available in 200 mg, 300 mg, and 400 mg strengths.[14]
• Tablets: Available in 250 mg and 500 mg strengths. The 500 mg tablet is scored, allowing it to be broken in half to facilitate more precise weight-based dosing.[14]
• Brand Names: In the United States and internationally, UDCA is known by numerous brand names, including Actigall, Urso, Urso Forte, Reltone, and Urso DS.[6] Other global trade names include Ursofalk, Urdox, and Ursocol, among others.[1]

Table 1: Physicochemical Properties of Ursodeoxycholic Acid

Property	Value	Source(s)
IUPAC Name	(3α,5β,7β)-3,7-dihydroxycholan-24-oic acid	6
Common Synonym	Ursodiol	1
CAS Number	128-13-2	13
DrugBank ID	DB01586	5
Molecular Formula	C24​H40​O4​	6
Average Molecular Weight	392.57 g/mol	5
Appearance	White to almost-white crystalline powder	15
Melting Point	203-204 °C	18
Water Solubility	Practically insoluble (20 mg/L at 20°C)	15
Ethanol Solubility	Freely soluble (50 mg/mL)	18
pKa	~5.04	18

III. Pharmacological Profile: A Multifaceted Mechanism of Action

The therapeutic efficacy of Ursodeoxycholic acid is not derived from a single, targeted interaction but from a confluence of pleiotropic effects that collectively address the pathophysiology of cholestatic liver disease and cholesterol gallstones. These mechanisms can be broadly categorized into anticholelithic, cytoprotective/choleretic, and immunomodulatory actions. The foundation of these biological effects is the drug's inherent hydrophilicity, which allows it to safely and fundamentally alter the bile acid environment in a way that endogenous bile acids cannot.

A. Anticholelithic and Cholesterol-Lowering Effects

UDCA's ability to dissolve cholesterol gallstones is a result of its concerted action on the three key determinants of biliary cholesterol saturation.

First, UDCA suppresses the liver's synthesis and secretion of cholesterol into bile.[5] Second, it concurrently inhibits the absorption of cholesterol molecules from the intestine.[1] This dual blockade on the entry of cholesterol into the enterohepatic circulation leads to a significant reduction in the overall cholesterol saturation of bile, shifting the thermodynamic balance away from cholesterol precipitation.[1]

Beyond simply lowering the cholesterol concentration, UDCA employs a unique physical mechanism. Although it is itself insoluble in aqueous media, it acts to disperse cholesterol within the bile, not only through the formation of traditional micelles but also by creating cholesterol-rich liquid crystals.[2] This process effectively increases the concentration at which cholesterol remains solubilized. The cumulative effect of these actions is the transformation of bile from a state that precipitates cholesterol to one that actively solubilizes it. This altered biochemical environment facilitates the gradual dissolution of cholesterol from the surface of existing radiolucent gallstones, providing a non-invasive therapeutic option.[2]

B. Cytoprotective and Choleretic Effects in Cholestasis

In cholestatic liver diseases such as PBC, the primary therapeutic benefit of UDCA stems from a cascade of events initiated by its favorable physicochemical properties. The accumulation of endogenous, hydrophobic bile acids (e.g., deoxycholic acid, chenodeoxycholic acid) is a central driver of liver injury in these conditions, as these molecules act as detergents that disrupt cell membranes and trigger cell death pathways.[2]

The therapeutic intervention begins with the oral administration of UDCA. Over time, this exogenous, hydrophilic bile acid becomes progressively enriched within the total bile acid pool, reaching concentrations of 30-50% with chronic dosing.[6] By competitively displacing the more toxic hydrophobic bile acids from the enterohepatic circulation, UDCA effectively shields hepatocytes (liver cells) and cholangiocytes (bile duct epithelial cells) from their damaging effects.[2]

This upstream modification of the bile acid pool enables a host of downstream cytoprotective mechanisms. UDCA has been shown to:

• Stabilize Cellular Membranes: It reduces the disruption of cholesterol-rich domains within the plasma membrane that are targeted by toxic bile acids.[2]
• Inhibit Apoptosis: UDCA actively counteracts programmed cell death. It achieves this by modulating mitochondrial function, specifically by preventing mitochondrial membrane perturbation, inhibiting the translocation of pro-apoptotic proteins like Bax, and reducing the release of cytochrome c, a key initiator of the caspase cascade.[2]
• Reduce Oxidative Stress: It attenuates the production of damaging reactive oxygen species (ROS) by resident liver macrophages (Kupffer cells), thereby mitigating a major source of inflammation and cellular injury.[6]

Complementing this direct cellular protection is UDCA's potent choleretic effect—the stimulation of bile flow.[3] This is not merely a passive consequence of increased bile acid concentration but an active process. UDCA is thought to increase intracellular calcium levels in hepatocytes, which in turn stimulates the activity of key canalicular transport proteins, such as the Bile Salt Export Pump (BSEP), and promotes vesicular exocytosis.[2] This enhanced secretion serves a dual purpose: it physically flushes toxic bile acids out of the liver, and it dilutes the concentration of any remaining toxic molecules in the biliary tree, further reducing their potential for harm. These mechanisms are not independent but are interconnected; the choleretic action directly enhances the cytoprotective environment.

C. Immunomodulatory and Anti-inflammatory Actions

In autoimmune liver diseases like PBC, the immunomodulatory properties of UDCA are particularly relevant. Experimental evidence demonstrates that UDCA can suppress certain immune responses, such as phagocytosis by immune cells.[1] Furthermore, it has been shown to reduce the expression of pro-inflammatory cytokines, including tumor necrosis factor-alpha (TNF-α) and various interleukins (IL-1, IL-2, IL-6), which are key mediators of the inflammatory damage that drives disease progression.[4]

These anti-inflammatory effects extend to the gastrointestinal tract. UDCA has been shown to exert protective effects on human colonic epithelial cells, partly through the regulation of antimicrobial peptides known as defensins and by actively promoting the restitution of epithelial wounds.[1] This has led to an intriguing area of research concerning its role in colon health. While certain secondary bile acids, such as deoxycholic acid, are known to be pro-tumorigenic in the colon, UDCA is thought to have chemopreventive properties. This may be achieved by inducing cellular differentiation or cellular senescence in colon epithelial cells, potentially counteracting the proliferative signals that can lead to cancer.[1] This highlights the nuanced and often opposing roles that different bile acids play in cellular regulation.

IV. Pharmacokinetics: Absorption, Distribution, Metabolism, and Excretion (ADME)

The clinical efficacy and safety of Ursodeoxycholic acid are intrinsically linked to its unique pharmacokinetic profile, which is dominated by extensive and efficient recycling through the enterohepatic circulation. This process dictates its slow accumulation, long half-life, and complex metabolic fate.

Absorption

Following oral administration, UDCA is absorbed from the gastrointestinal tract, primarily in the small intestine, through a process of passive diffusion.[6] The absorption is incomplete, with bioavailability estimates varying, though some sources suggest it can be as high as 60-90%.[21] Once absorbed into the portal circulation, UDCA undergoes a substantial first-pass extraction by the liver. In individuals with healthy liver function, approximately 50% of the absorbed dose is extracted from the portal blood during its initial passage. The extent of this extraction decreases as the severity of liver disease increases, which can alter the drug's systemic exposure.[6]

A key clinical consideration is the effect of food on absorption. Administration of UDCA with meals is recommended because food stimulates gallbladder contraction and the release of endogenous bile acids. These bile acids help to solubilize the poorly water-soluble UDCA into micelles, thereby enhancing its absorption.[2]

Distribution

The volume of distribution for UDCA has not been precisely determined but is expected to be small. This is because the drug does not distribute widely throughout the body's tissues; instead, it is highly concentrated within the compartments of the enterohepatic circulation—namely the bile, gallbladder, and intestines.[6] In the systemic circulation, unconjugated UDCA is highly bound to plasma proteins, with a binding fraction of at least 70%. Information regarding the protein binding of its conjugated metabolites is not available.[6]

Metabolism

The metabolism of UDCA is a complex, multi-step process centered on its continuous recycling between the liver and the intestine. After hepatic uptake, UDCA is conjugated with the amino acids glycine or taurine to form glycoursodeoxycholic acid (GUDCA) and tauroursodeoxycholic acid (TUDCA).[6] These water-soluble conjugates are then actively secreted into the bile.

Upon reaching the intestine, these conjugates can be reabsorbed or undergo further transformation by the gut microbiota. Intestinal enzymes can deconjugate them back to free UDCA, which is then available for reabsorption into the portal circulation, completing the cycle.[6]

A critical metabolic step occurs in the colon, where unabsorbed UDCA is subjected to 7-dehydroxylation by anaerobic bacteria. This process converts UDCA into lithocholic acid (LCA), a secondary bile acid known to be hepatotoxic in certain species.[5] The safety of UDCA therapy is therefore critically dependent on the body's ability to manage this toxic metabolite. While approximately 80% of the formed LCA is excreted directly in the feces, the remaining 20% is reabsorbed.[5] This reabsorbed LCA is efficiently detoxified in the liver through sulfation at the 3-hydroxyl group. The resulting sulfated lithocholyl conjugates are poorly soluble, readily secreted into bile, and subsequently eliminated in the feces without being reabsorbed.[5] This detoxification pathway underscores a crucial point: the safety of UDCA is not solely an intrinsic property of the drug itself but relies on the functional integrity of two key biological systems—a balanced gut microbiome to mediate the initial transformations and, most importantly, an efficient hepatic sulfation capacity to neutralize the toxic byproduct. Any impairment in these systems could theoretically increase a patient's susceptibility to LCA-induced toxicity.

Excretion

The primary route of elimination for UDCA and its metabolites is fecal excretion.[5] The drug and its byproducts are effectively cleared from the body via the biliary-fecal route. Renal elimination represents a very minor pathway, accounting for less than 1% of total excretion. However, in patients with severe cholestatic liver disease where biliary excretion is impaired, the urinary excretion of UDCA may increase.[6]

Half-life and Steady State

The extensive and efficient enterohepatic recycling of UDCA results in a prolonged elimination half-life, estimated to be between 3.5 and 5.8 days.[6] This slow elimination and continuous recirculation mean that it takes a significant amount of time for the drug to accumulate and reach a new equilibrium within the bile acid pool. Consequently, steady-state concentrations in the bile are typically achieved only after approximately three weeks of consistent, daily dosing.[6] This pharmacokinetic profile directly informs the clinical use of UDCA as a chronic therapy and highlights the importance of patient adherence. Missing doses can disrupt the therapeutic enrichment of the bile acid pool, undermining the drug's efficacy, which depends on maintaining this new, favorable biochemical state.

V. Approved and Off-Label Therapeutic Applications

The clinical use of Ursodeoxycholic acid spans a range of hepatobiliary disorders, with a clear distinction between indications that have received formal approval from regulatory bodies like the U.S. FDA and the European Medicines Agency (EMA), and those that are widely used off-label based on clinical experience and evolving evidence. A point of potential confusion in the literature is the FDA-approved status for gallstone dissolution. This is resolved by understanding that regulatory approvals are often formulation-specific: in the U.S., UDCA capsules (e.g., Actigall) are approved for gallstone-related indications, whereas UDCA tablets (e.g., Urso, Urso Forte) are approved for Primary Biliary Cholangitis.[3]

A. FDA- and EMA-Approved Indications

• Primary Biliary Cholangitis (PBC): The treatment of PBC is a primary, FDA-approved indication for UDCA tablets.[1] The standard recommended adult dosage is 13-15 mg/kg/day, administered in two to four divided doses with food.[24] UDCA is the established first-line therapy for PBC, with robust evidence demonstrating its ability to significantly improve serum biochemical markers of cholestasis and liver injury, such as alkaline phosphatase (ALP) and bilirubin.[2] More importantly, long-term studies and meta-analyses have shown that treatment with UDCA can delay histological progression, reduce the development of cirrhosis, and prolong transplant-free survival.[1] While its impact on disease progression is well-documented, its effect on improving symptoms like pruritus (itching) and fatigue is considered less consistent.[1]
• Gallstone Dissolution: UDCA capsules are FDA-approved for the medical dissolution of gallstones.[6] This indication is reserved for a select patient population who are poor candidates for or refuse surgery (cholecystectomy). The key criteria for treatment eligibility are the presence of radiolucent (i.e., non-calcified and cholesterol-rich) gallstones, typically less than 20 mm in diameter, and a functioning gallbladder.[2] The usual dosage for this indication is 8-10 mg/kg/day, often divided into 2 or 3 doses.[3] Treatment is a long-term process, often requiring months to years for complete dissolution.
• Gallstone Prevention: UDCA capsules are also FDA-approved for the prevention of gallstone formation in a specific high-risk group: obese patients undergoing rapid weight loss, such as after bariatric surgery or on very-low-calorie diets.[1] Rapid weight loss can lead to biliary cholesterol oversaturation and gallbladder stasis, creating an environment ripe for stone formation. The standard prophylactic dose is 300 mg administered twice daily.[3]
• Inborn Errors of Bile Acid Synthesis (EMA): In Europe, bile acid therapy has a specific orphan drug approval for the treatment of rare genetic disorders of primary bile acid synthesis, such as 3β-Hydroxy-Δ5-C27-steroid oxidoreductase deficiency. This highlights its critical role in managing certain pediatric cholestatic diseases where endogenous bile acid production is faulty.[39]

B. Common Off-Label and Investigational Uses

The favorable safety profile and plausible mechanisms of action of UDCA have led to its widespread off-label use in numerous conditions, creating a landscape where clinical practice often precedes definitive, large-scale trial evidence.

• Primary Sclerosing Cholangitis (PSC): This remains one of the most common yet controversial off-label uses of UDCA. It is frequently prescribed to improve abnormal liver enzyme levels, and many experts still recommend moderate doses (13-15 mg/kg/day) for this purpose.[3] However, the evidence for a long-term clinical benefit on disease progression or survival is mixed and unproven.[3] Critically, this use comes with a significant safety caveat: high-dose UDCA (28-30 mg/kg/day) was found in a major clinical trial to be harmful, increasing the risk of death and the need for liver transplantation by 2.3-fold. This has led to strong warnings against the use of high doses in PSC patients.[1]
• Intrahepatic Cholestasis of Pregnancy (ICP): UDCA is the most commonly used off-label treatment for ICP, a condition characterized by debilitating pruritus and elevated serum bile acids in the mother.[1] It has been shown to effectively reduce itching and lower maternal bile acid levels. Some evidence suggests it may also reduce the rate of preterm births, although its impact on other adverse fetal outcomes is less certain.[1]
• Cystic Fibrosis-Associated Liver Disease (CFLD): UDCA has an orphan drug designation for this indication and is used off-label to manage the associated cholestatic liver disease.[1] However, its efficacy remains a subject of debate, with a 2021 study finding no significant reduction in the incidence of portal hypertension in patients treated with UDCA.[1]
• Metabolic Dysfunction-Associated Fatty Liver Disease (MAFLD/NAFLD): The role of UDCA in NAFLD (now often termed MAFLD) is under active investigation. Some studies have demonstrated improvements in liver enzyme levels, suggesting a potential benefit.[8] A clinical trial is currently recruiting to compare the efficacy of UDCA against ademetionine in patients with MAFLD and an enlarged liver (hepatomegaly).[42]
• Other Investigational Uses: The application of UDCA continues to expand into other areas. It is used off-label for bile reflux gastritis [1] and for the prevention of hepatic sinusoidal obstruction syndrome (also known as veno-occlusive disease) in patients undergoing hematopoietic stem cell transplantation.[38] More recently, its role as a secondary bile acid that can inhibit the germination of Clostridioides difficile spores has prompted clinical trials investigating its use in preventing recurrent C. diff infection.[15]

The extensive off-label use of UDCA underscores a persistent gap between widespread clinical practice and the high-level evidence generated by large, randomized controlled trials. This gap highlights a critical need for further research to formally validate or refute these common uses, thereby establishing clear risk-benefit profiles and optimizing patient care.

Table 2: Dosing Regimens for Key Therapeutic Indications of Ursodeoxycholic Acid

Indication	Regulatory Status (U.S.)	Recommended Dosage	Key Administration Notes	Source(s)
Primary Biliary Cholangitis (PBC)	Approved (Tablets)	13-15 mg/kg/day	Administer in 2-4 divided doses with food.	24
Gallstone Dissolution	Approved (Capsules)	8-10 mg/kg/day	Administer in 2-3 divided doses.	3
Gallstone Prevention	Approved (Capsules)	300 mg twice daily	For obese patients during rapid weight loss.	3
Intrahepatic Cholestasis of Pregnancy (ICP)	Off-Label	10-15 mg/kg/day (can be titrated up to 21 mg/kg/day)	Administer in 2-3 divided doses; continue until delivery.	9
Primary Sclerosing Cholangitis (PSC)	Off-Label	13-15 mg/kg/day (moderate dose)	High doses (>20 mg/kg/day) are not recommended due to safety concerns.	1
Cystic Fibrosis Liver Disease	Off-Label (Orphan Designation)	10-20 mg/kg/day	Administer in divided doses.	1
Prevention of Hepatic Sinusoidal Obstruction Syndrome	Off-Label	12 mg/kg/day or 600 mg/day	Administer in 2 divided doses; start before conditioning regimen.	38

VI. The Evolving Clinical Trial Landscape: From Hepatology to Neurology and Infectious Disease

While Ursodeoxycholic acid has a well-established role in hepatology, its therapeutic story is far from complete. The drug's fundamental cytoprotective mechanisms and excellent long-term safety profile have made it an attractive candidate for repurposing in a diverse array of conditions far beyond the liver. The current clinical trial landscape reflects this evolution, with research spanning confirmatory studies in liver disease to pioneering investigations in neurology and infectious disease. This expansion is largely enabled by the decades of safety data and low cost associated with UDCA, which lower the barriers for launching trials in new indications compared to novel, unproven compounds.

Pivotal and Confirmatory Trials in Hepatology

The foundation of UDCA's use was built on clinical trials demonstrating its efficacy in PBC and gallstone disease.[2] Research in this area continues, focusing on optimizing therapy for patients who do not achieve an adequate response to standard treatment. For instance, clinical trials have explored the efficacy of higher doses (18-22 mg/kg/day) in patients with refractory PBC, aiming to determine if a greater therapeutic effect can be achieved without compromising safety.[45]

Furthermore, the field is moving towards combination therapies. A landmark Phase 3 trial (BEZURSO) investigated the addition of the fibrate bezafibrate to UDCA for PBC patients with an incomplete biochemical response. The study showed that combination therapy was significantly more effective at reducing liver enzyme levels than UDCA alone, establishing a new therapeutic option for this patient population.[46] This trend of building upon UDCA as a foundational therapy is further cemented by the recent FDA accelerated approval of seladelpar (Livdelzi). This novel PPAR-delta agonist is indicated specifically for the treatment of PBC

in combination with UDCA in adults with an inadequate response, or as monotherapy for those intolerant to UDCA. This positions UDCA as the undisputed first-line standard of care, with newer agents being added to it rather than replacing it.[47]

Investigational Trials in Novel Therapeutic Areas

The most dynamic area of UDCA research involves its repurposing for extrahepatic diseases, targeting its fundamental mechanisms of action in new pathological contexts.

• Neurodegenerative Disorders (Parkinson's Disease): A significant leap for UDCA has been its investigation in Parkinson's Disease (PD). Mitochondrial dysfunction—the failure of the cell's energy-producing organelles—is a key pathological driver of neuron loss in PD. Based on preclinical work showing that UDCA could rescue mitochondrial function in PD patient-derived cells, the Phase 2 "UP" Study (NCT03840005) was launched.[48] This double-blind, placebo-controlled trial was designed as a "proof of concept" study. A key feature was the use of a high dose (30 mg/kg/day), double the standard liver disease dose, to ensure adequate penetration into the brain. The trial, which ran for 48 weeks, successfully met its primary endpoint, demonstrating that this high dose was safe and well-tolerated by people with PD. While the study was not powered for efficacy, exploratory sub-studies yielded promising signals, including evidence of improved brain energy metabolism (as measured by magnetic resonance spectroscopy) and potential improvements in gait for participants taking UDCA.[48] These results provide a strong rationale for larger, definitive Phase 3 trials to determine if UDCA can slow the progression of PD, representing a major potential expansion of its therapeutic scope from a liver drug to a neuroprotective agent.
• Infectious Diseases (COVID-19): During the COVID-19 pandemic, UDCA emerged as a potential therapeutic based on strong biological plausibility. The proposed mechanism is that UDCA, by acting as an antagonist to the farnesoid X receptor (FXR), downregulates the expression of angiotensin-converting enzyme 2 (ACE2), the primary cellular receptor used by the SARS-CoV-2 virus to enter host cells.[50] By reducing the number of these "doorways," UDCA could theoretically limit viral entry and replication. This hypothesis has led to a flurry of research, but the results from observational studies have been conflicting. Some large, population-based cohort studies found that UDCA use was associated with a significant reduction in the risk of severe COVID-19 outcomes, including hospitalization and death.[50] In contrast, other studies reported no discernible benefit.[51] This controversy has led to prominent calls for well-designed, randomized controlled trials to definitively assess the value of UDCA as a prophylactic or therapeutic agent for COVID-19.[4]
• Other Investigational Areas: The breadth of research continues to grow, with trials exploring UDCA's utility in other conditions driven by cholestasis, inflammation, or cellular stress:
• Hepatic Sarcoidosis: A pilot study (NCT03602976) was designed to evaluate the efficacy of UDCA in improving liver function and quality of life in patients with this rare inflammatory condition, which often presents with a cholestatic pattern of liver injury.[53]
• Chronic Heart Failure (CHF): A completed crossover study (NCT00285597) investigated the effects of UDCA on peripheral blood flow and immune function in patients with stable CHF, exploring its potential to modulate the inflammatory state associated with the disease.[54]
• Recurrent Clostridioides difficile Infection: Based on evidence that secondary bile acids can inhibit the germination of C. diff spores, a key step in disease recurrence, a clinical trial (NCT05526807) is underway to assess whether UDCA can prevent recurrent infections after standard antibiotic treatment.[15]

This diverse and expanding clinical trial portfolio demonstrates a paradigm shift in the perception of UDCA. Researchers are increasingly looking beyond its role in the liver and are instead targeting its fundamental cytoprotective, anti-inflammatory, and metabolic properties to address unmet needs in a wide range of human diseases.

Table 4: Overview of Key Investigational Clinical Trials for Ursodeoxycholic Acid

Condition	ClinicalTrials.gov ID	Study Phase	Key Intervention (Dose)	Primary Outcome	Status / Key Finding	Source(s)
Parkinson's Disease	NCT03840005	Phase 2	30 mg/kg/day	Safety and Tolerability	Completed. Drug was safe and well-tolerated. Showed promising signals of improved brain energy metabolism.	48
COVID-19 Prevention/Treatment	N/A (Observational Studies & Trial Proposals)	N/A	Variable	Incidence of severe disease, hospitalization, or death	Conflicting observational data. RCTs have been proposed to resolve controversy.	4
Recurrent C. difficile Infection	NCT05526807	Feasibility Study	Not specified	Tolerability and Adherence	Active, not recruiting. Aims to prevent recurrence.	44
Hepatic Sarcoidosis	NCT03602976	Pilot Study	Not specified	Reduction in Alkaline Phosphatase	Active, not recruiting. Evaluates efficacy in improving liver function.	53
Refractory Primary Biliary Cholangitis	NCT03345589	Not specified	18-22 mg/kg/day vs. 13-15 mg/kg/day	Biochemical Remission	Unknown status. Investigating higher doses for non-responders.	45
Chronic Heart Failure	NCT00285597	Not specified	1000 mg/day	Peripheral Blood Flow and Immune Function	Completed. Investigated effects on inflammation and vascular function.	54

VII. Safety, Tolerability, and Risk Management

Ursodeoxycholic acid is generally regarded as a safe and well-tolerated medication, a reputation built over decades of clinical use in chronic liver diseases. However, like all therapeutic agents, it has specific contraindications, potential adverse effects, and requires appropriate monitoring to ensure patient safety. The drug's safety limitations are often a direct reflection of its mechanisms of action; for example, its choleretic (bile-flow-stimulating) effect makes it unsuitable for use in cases of complete biliary obstruction, where it could dangerously increase ductal pressure.

Contraindications

The use of UDCA is absolutely contraindicated in certain clinical scenarios where it is either ineffective or potentially harmful:

• Stone Composition: UDCA is specifically a cholesterol gallstone solubilizing agent. It is therefore contraindicated in patients with calcified, radio-opaque gallstones or radiolucent bile pigment stones, as it will not dissolve them.[14]
• Biliary Obstruction and Acute Inflammation: Patients with complete biliary tract occlusion (e.g., of the common bile duct or cystic duct) or those with acute inflammation of the gallbladder (cholecystitis) or biliary tract (cholangitis) should not receive UDCA. It is also contraindicated in patients with a biliary-gastrointestinal fistula or those who have compelling reasons for cholecystectomy.[3]
• Hypersensitivity: A known hypersensitivity or allergy to bile acids or any component of the formulation is a clear contraindication.[20]

Warnings and Precautions

Several situations warrant caution and careful patient monitoring during UDCA therapy:

• Liver Function Monitoring: While UDCA therapy is typically associated with an improvement in liver biochemical tests, it is recommended that liver function (including γ-GT, ALP, AST, ALT) and bilirubin levels be monitored periodically. A common schedule is every month for the first three months of therapy and every six months thereafter. Treatment discontinuation should be considered if these parameters increase to a clinically significant level in patients who had previously stable liver function.[26]
• Advanced Liver Disease: Caution should be exercised when initiating UDCA in patients with advanced, decompensated liver disease, such as those with variceal bleeding, hepatic encephalopathy, or ascites. Although rare, there have been postmarketing reports of clinical decompensation in this vulnerable population, and such patients should receive appropriate specific treatment for their complications.[8]
• Enteroliths: There have been rare postmarketing reports of patients developing enteroliths (bezoars), which are stonelike masses in the intestine that can cause obstructive symptoms. These events have occurred in patients with underlying medical conditions that predispose them to intestinal stenosis (narrowing) or stasis (slowed transit), such as Crohn's disease or prior surgical enteroanastomoses. If a patient on UDCA presents with obstructive gastrointestinal symptoms, the medication should be withheld pending a full clinical evaluation.[20]

Adverse Effects

The adverse effect profile of UDCA is generally mild, with gastrointestinal symptoms being the most common.

• Common (≥5% incidence):
• Gastrointestinal: Diarrhea is the most frequently reported adverse reaction, occurring in a significant percentage of patients in clinical trials. Other common digestive complaints include dyspepsia (indigestion), nausea, and abdominal pain.[6]
• Neurological: Headache and dizziness are also commonly reported.[20]
• Other: Back pain and upper respiratory tract infections have been noted with relatively high frequency in clinical trials, though often at rates similar to placebo.[20] In PBC trials, some patients have occasionally reported right upper quadrant abdominal pain or a temporary exacerbation of pruritus upon starting therapy.[1]
• Less Common (1-10% incidence):
• Dermatologic: Alopecia (hair thinning or loss) and rash can occur.[1]
• Gastrointestinal: Constipation and flatulence are reported less frequently than diarrhea.[20]
• Hematologic: Leukopenia (low white blood cell count) and thrombocytopenia (low platelet count) have been observed.[26]
• Rare and Postmarketing Reports:
• Hepatobiliary: Aggravation of pre-existing jaundice has been reported.
• Immune System: Hypersensitivity reactions, including urticaria (hives), facial edema, and angioedema, have been reported.[26]
• Musculoskeletal: Myalgia (muscle pain) has been noted.[27]

Overdosage

Neither accidental nor intentional overdosage with UDCA has been widely reported in the literature. The most likely and prominent manifestation of a significant overdose would be severe diarrhea. Management of an overdose should be symptomatic, focusing on fluid and electrolyte replacement as needed.[5]

VIII. Drug-Drug and Drug-Food Interactions

The clinical effectiveness and safety of Ursodeoxycholic acid can be significantly influenced by concomitant medications and food. Interactions can be pharmacokinetic, affecting the absorption or metabolism of UDCA or other drugs, or pharmacodynamic, where the biological effects of the drugs interfere with one another. A thorough understanding of these interactions is crucial for safe and effective prescribing.

Pharmacokinetic Interactions

• Agents Reducing UDCA Absorption: This is the most clinically significant and well-documented category of interactions. Several compounds can bind to UDCA within the gastrointestinal lumen, preventing its absorption and thereby reducing its therapeutic efficacy.
• Bile Acid Sequestrants: Resins such as cholestyramine, colestipol, and colesevelam are designed to bind bile acids and will also bind exogenously administered UDCA.
• Aluminum-Based Antacids: Antacids containing aluminum hydroxide or similar compounds can adsorb bile acids.
• Management: To mitigate this interaction, it is strongly recommended that these agents be administered at least 2 hours before or 2 hours after the UDCA dose, allowing time for UDCA to be absorbed without interference.[5]
• Transporter- and Enzyme-Mediated Interactions: UDCA is a substrate, inhibitor, and/or inducer of several drug-metabolizing enzymes and transport proteins, creating a potential for complex interactions.
• Cytochrome P450 (CYP) 3A Subfamily: UDCA has been identified as an inducer of the CYP3A subfamily. This could theoretically accelerate the metabolism of other drugs that are CYP3A substrates, potentially lowering their plasma concentrations and reducing their efficacy.[32]
• Membrane Transporters: UDCA interacts with several key transporters involved in drug disposition. It is a substrate, inhibitor, and inducer of the Bile Salt Export Pump (BSEP), which could lead to complex interactions with other BSEP substrates like cyclosporine or rifampicin.[32] It is also both a substrate and an inhibitor of the Solute Carrier Organic Anion Transporter family member 1A2 (SLCO1A2, also known as OATP1A2), which could affect the pharmacokinetics of drugs like methotrexate and fexofenadine.[32]
• UDCA's Impact on Other Drugs:
• Cyclosporine: UDCA has been reported to increase the absorption and systemic levels of cyclosporine. Therefore, in patients receiving both drugs, monitoring of cyclosporine concentrations is necessary to avoid toxicity.[5]
• Nitrendipine: Conversely, UDCA can cause a decrease in the absorption of the calcium channel blocker nitrendipine, potentially reducing its therapeutic effect.[6]

Pharmacodynamic Interactions

• Agents Counteracting UDCA Efficacy: Certain drugs have pharmacological effects that directly oppose the therapeutic goals of UDCA, particularly for gallstone dissolution.
• Estrogens and Oral Contraceptives: Estrogenic compounds increase hepatic cholesterol secretion and promote the formation of cholesterol-saturated bile. This encourages gallstone formation and directly counteracts the cholesterol-desaturating effect of UDCA.[5]
• Lipid-Lowering Agents (Fibrates): Drugs like clofibrate and other fibrates can also increase biliary cholesterol secretion, thereby working against the mechanism of UDCA and potentially reducing its effectiveness for dissolving gallstones.[5]

Food Interactions

Unlike many drugs that have negative interactions with food, UDCA benefits from it. As detailed in the pharmacokinetics section, administration with food is generally recommended. Food intake stimulates the secretion of endogenous bile, which helps to form micelles that solubilize the poorly water-soluble UDCA, thereby enhancing its absorption and bioavailability.[2]

Table 3: Summary of Clinically Significant Drug Interactions with Ursodeoxycholic Acid

Interacting Agent / Class	Mechanism of Interaction	Clinical Effect on UDCA or Other Drug	Management Recommendation	Source(s)
Bile Acid Sequestrants (Cholestyramine, Colestipol)	Adsorption in GI tract	Decreased absorption and efficacy of UDCA.	Administer UDCA at least 2 hours before or after the sequestrant.	5
Aluminum-Based Antacids	Adsorption in GI tract	Decreased absorption and efficacy of UDCA.	Separate administration times by at least 2 hours.	14
Estrogens / Oral Contraceptives	Pharmacodynamic antagonism (increase biliary cholesterol secretion)	Counteracts the gallstone-dissolving effect of UDCA.	Consider alternative non-hormonal contraception for patients treated for gallstones.	5
Fibrates (Clofibrate, Fenofibrate)	Pharmacodynamic antagonism (increase biliary cholesterol secretion)	May counteract the gallstone-dissolving effect of UDCA.	Monitor for decreased therapeutic effect.	5
Cyclosporine	Increased GI absorption of cyclosporine	Increased plasma levels and potential toxicity of cyclosporine.	Monitor cyclosporine concentrations and adjust dose as needed.	5
Nitrendipine	Decreased GI absorption of nitrendipine	Decreased plasma levels and potential reduced efficacy of nitrendipine.	Monitor clinical response (e.g., blood pressure).	6
CYP3A Substrates	Induction of CYP3A enzymes by UDCA	Potential for decreased plasma levels and efficacy of the substrate drug.	Monitor for efficacy of the co-administered CYP3A substrate.	32

IX. Use in Special Populations

The use of Ursodeoxycholic acid in special populations—including pediatric patients, the elderly, and during pregnancy and lactation—is largely governed by a balance between clinical necessity and the limitations of available evidence. For many of these groups, widespread off-label use has outpaced formal regulatory approval, creating a landscape where clinical judgment is paramount.

A. Pediatric Patients

The use of UDCA in children is a prominent example of practice driven by medical need in the absence of broad regulatory approval. In the U.S. and Canada, UDCA is not formally approved by regulatory bodies like the FDA and Health Canada for most pediatric indications, as its safety and effectiveness have not been established in large-scale trials for this population.[1]

Despite this, UDCA has been used off-label for decades as an adjunctive therapy in a variety of pediatric cholestatic liver diseases.[31] This use is supported by a body of evidence from smaller trials, retrospective studies, and case series. Key off-label applications include:

• Biliary Atresia: Following a Kasai portoenterostomy procedure, UDCA is often used at doses of 10-20 mg/kg/day to promote bile flow and protect against cholangitis.[26]
• Parenteral Nutrition-Associated Cholestasis (PNAC): In infants, particularly premature neonates, who develop cholestasis from long-term intravenous nutrition, UDCA has been used at doses ranging from 10 to 30 mg/kg/day with the aim of improving bile flow and resolving jaundice, although efficacy results have been variable.[31]
• Genetic Cholestatic Syndromes: For inherited conditions like Progressive Familial Intrahepatic Cholestasis (PFIC), UDCA at doses of 20-30 mg/kg/day has been shown to improve liver function and clinical status in a significant proportion of affected children.[59]
• Cystic Fibrosis-Associated Liver Disease: UDCA is used to manage the hepatobiliary complications of cystic fibrosis, though its long-term impact on disease progression remains under investigation.[1]

The use in neonates and young infants remains particularly controversial. While many studies and a 2022 meta-analysis suggest that UDCA is effective and safe for improving biochemical markers of cholestasis in children [60], some researchers have raised concerns about a lack of efficacy and potential for harm in the neonatal population, especially at higher doses.[1] This highlights the ongoing need for more robust pediatric clinical trials.

B. Geriatric Patients

There are no specific dosing adjustments provided for geriatric patients in manufacturer labeling.[61] Health Canada has not authorized a specific indication for geriatric use.[56] However, clinical trials for UDCA have included patients over the age of 65, and subgroup analyses have not revealed significant differences in efficacy or safety compared to younger populations.[20] While no major age-related differences in response have been identified, standard pharmacological practice advises cautious dosing in the elderly, starting at the lower end of the dosage range, to account for potential greater sensitivity and the higher likelihood of comorbid conditions or concomitant medications.[20]

C. Pregnancy and Lactation

• Pregnancy: The use of UDCA during pregnancy is a complex issue where clinical practice and official labeling can diverge. Its most common use is the off-label treatment of Intrahepatic Cholestasis of Pregnancy (ICP), a condition that poses risks to the fetus.[1] Based on several decades of observational data and case series, the use of UDCA (typically initiated in the second or third trimester for ICP) has not been associated with an increased risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes.[27] For this reason, many clinical guidelines and expert bodies consider it safe to use for ICP under specialist supervision.[29] However, due to the absence of large, formal, randomized controlled trials in pregnant women, some official drug labels from regulatory agencies maintain cautionary language, contraindicate its use, or assign a pregnancy category (e.g., Australia's B3) that reflects limited human data.[20] Therefore, the decision to use UDCA during pregnancy requires a careful risk-benefit assessment by the treating physician.
• Lactation: The use of UDCA during breastfeeding is generally considered safe.[62] UDCA is a natural, albeit minor, component of human milk. Studies measuring bile acid levels in the milk of mothers taking therapeutic doses of UDCA have found that while the proportion of UDCA in the milk increases, the total amount transferred to the infant is clinically negligible and far below therapeutic doses given directly to neonates.[62] There are no reports of adverse effects in breastfed infants whose mothers were taking UDCA. Therefore, it is not expected to pose a risk to the nursing infant, and no special precautions are typically required.[62]

X. Conclusion and Future Directions

Synthesis of Profile

Ursodeoxycholic acid (UDCA) has firmly established itself as a unique and valuable therapeutic agent in the field of hepatology. Arising from origins in traditional medicine, it has evolved into a well-characterized, evidence-based pharmaceutical defined by its pleiotropic mechanisms of action. Its clinical value is rooted in its fundamental physicochemical property of hydrophilicity, which allows it to safely and effectively remodel the endogenous bile acid pool. This primary action enables a cascade of downstream effects—including cytoprotection, anti-apoptosis, choleresis, and immunomodulation—that collectively shield the liver and biliary system from the damage wrought by cholestasis and cytotoxic bile acids.

As a result, UDCA stands as the undisputed, robust first-line therapy for Primary Biliary Cholangitis, with proven benefits on biochemical markers and long-term, transplant-free survival. It also provides a vital non-surgical treatment option for the dissolution of cholesterol gallstones and a prophylactic strategy for their prevention in high-risk individuals. Its tolerability and long-term safety profile are excellent, further cementing its role as a foundational drug in the management of these conditions.

The Future of UDCA

While its place in hepatology is secure, the most compelling chapter in the story of UDCA may be the one that is still being written. The future of this remarkable molecule lies in its therapeutic repurposing for a wide range of extrahepatic diseases. The growing understanding that its mechanisms of action are not liver-specific but target fundamental cellular processes like mitochondrial function, apoptosis, and inflammation has opened the door to new applications.

The strong biological rationale and promising early-phase clinical data for its use in neurodegenerative disorders, particularly Parkinson's Disease, represent a potential paradigm shift, transforming UDCA from a "liver drug" to a potential neuroprotective agent.[48] Similarly, its proposed mechanism for interfering with viral entry has sparked intense (though currently inconclusive) investigation into its role in infectious diseases like COVID-19.[4] These explorations, along with ongoing research in conditions ranging from cystic fibrosis to metabolic fatty liver disease, suggest that the full therapeutic potential of UDCA has yet to be realized.

Call for Future Research

The expansion of UDCA's use into both established off-label indications and novel investigational areas has created a clear and pressing need for further high-quality research. To bridge the existing gap between widespread clinical practice and the formal evidence base, large-scale, well-designed, randomized controlled trials are essential. Such trials are critically needed to definitively establish the efficacy, optimal dosing, and long-term safety of UDCA in conditions like Primary Sclerosing Cholangitis and NAFLD/MAFLD, where its use is common but its benefit remains unproven.

Moreover, for the exciting new frontiers in neurology and other fields, rigorous Phase 3 trials are the necessary next step to validate the promising signals seen in early studies. Only through this commitment to robust clinical investigation can the full potential of this ancient remedy be harnessed by modern medicine, ensuring that its benefits are delivered to all patients who stand to gain from its unique protective properties.

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