Chenodeoxycholic Acid (DB06777): A Comprehensive Pharmacological and Clinical Monograph

Executive Summary

Chenodeoxycholic acid (CDCA) is an endogenous primary bile acid synthesized in the liver from cholesterol, playing a fundamental role in lipid digestion and metabolic homeostasis. Beyond its physiological function, CDCA has been developed as a therapeutic agent, identified by DrugBank ID DB06777, with a unique and evolving clinical profile. This monograph provides a comprehensive analysis of its chemistry, pharmacology, clinical applications, safety, and regulatory status.

Initially approved for the dissolution of radiolucent cholesterol gallstones in patients with high surgical risk, CDCA's use in this indication has diminished due to modest efficacy rates, a high incidence of adverse effects, and the advent of superior therapeutic alternatives. However, a deeper understanding of its mechanism of action has led to a clinical renaissance for the drug. CDCA is now established as the first-line, life-altering replacement therapy for Cerebrotendinous Xanthomatosis (CTX), a rare, autosomal recessive lipid storage disease. In CTX, CDCA corrects the core biochemical defect, preventing irreversible neurological damage and other systemic complications.

The pharmacological actions of CDCA are primarily mediated through its potent agonist activity at the Farnesoid X Receptor (FXR), a nuclear receptor that governs the expression of genes involved in bile acid, cholesterol, and glucose metabolism. This mechanism underpins both its ability to desaturate biliary cholesterol for gallstone dissolution and its capacity to restore metabolic balance in CTX.

The safety profile of CDCA is notable, characterized by a high incidence of dose-dependent diarrhea and a significant risk of hepatotoxicity, which has led to a black box warning for its use in gallstone disease. Careful patient selection and systematic monitoring of liver function are therefore imperative during therapy.

The regulatory journey of CDCA exemplifies the impact of orphan drug legislation, which facilitated its approval for the rare disease CTX but also created a market monopoly that led to significant pricing controversies in Europe. Current research continues to explore the therapeutic potential of CDCA and its derivatives in a range of conditions, including chronic constipation, nonalcoholic fatty liver disease (NAFLD), and other metabolic disorders, underscoring its enduring importance as both a physiological signaling molecule and a versatile therapeutic agent.

Drug Identification and Physicochemical Profile

Nomenclature and Chemical Identifiers

Precise identification of a pharmaceutical substance is critical for research, clinical practice, and regulatory affairs. Chenodeoxycholic acid is known by a variety of names and is cataloged across numerous chemical and pharmacological databases.

• Generic Name: Chenodeoxycholic acid [1]
• Systematic IUPAC Name:  acid [2]
• Alternative Names & Synonyms: Chenodiol, chenodesoxycholic acid, chenocholic acid, -dihydroxy--cholan-24-oic acid, Anthropodeoxycholic Acid, CDCA, CDC, Chenix, Chenossil, Fluibil, Hekbilin, Kebilis, and Ulmenide [4]
• Brand Names: The compound is marketed under several brand names, including Chenodal, Chenodeoxycholic Acid Leadiant, and Ctexli.[1]
• Key Database Identifiers:
• DrugBank ID: DB06777 [1]
• CAS Number: 474-25-9 [1]
• InChIKey: RUDATBOHQWOJDD-BSWAIDMHSA-N [2]

Chemical Structure and Properties

The therapeutic activity and pharmacokinetic profile of chenodeoxycholic acid are direct consequences of its molecular structure and resulting physicochemical properties. It is a C24-steroid and a dihydroxy--cholanic acid, first isolated from the bile of the domestic goose, which is the origin of the "cheno" prefix (Greek:  = goose).[2]

The fundamental properties of CDCA are summarized in Table 1. Its chemical structure, defined by a steroid nucleus with two hydroxyl groups and a pentanoic acid side chain, confers an amphipathic character. This dual nature—possessing both hydrophobic (the steroid core) and hydrophilic (the hydroxyl and carboxyl groups) regions—is central to its physiological function.

The molecule's high lipophilicity, indicated by a LogP value of 4.15, and its very low aqueous solubility are defining features.[2] These characteristics are essential for its biological role in emulsifying non-polar dietary fats within the aqueous environment of the intestine.[8] At the same time, these properties present a significant challenge from a pharmaceutical perspective. For an orally administered drug to be effectively absorbed, it must first dissolve in the gastrointestinal fluids. The poor water solubility of CDCA necessitates careful formulation, often involving excipients that enhance dissolution. The clinical recommendation to administer the drug with food for gallstone treatment likely leverages the natural postprandial increase in bile secretion to aid in the solubilization and subsequent absorption of the exogenous CDCA.[10] Thus, the physicochemical properties of CDCA are not merely descriptive data points; they are the direct determinants of both its biological utility and the strategies required for its successful delivery as a therapeutic agent.

Table 1: Key Identifiers and Physicochemical Properties of Chenodeoxycholic Acid

Property	Value	Source(s)
DrugBank ID	DB06777	1
CAS Number	474-25-9	1
Chemical Formula		1
Average Molecular Weight	392.57 g/mol	1
Monoisotopic Weight	392.292659768 Da	1
Physical Description	White to off-white crystalline powder/solid	4
Melting Point	165–167 °C (range reported 119–171 °C)	2
Solubility in Water	89.9 mg/L (at 20 °C)	2
Solubility (Other)	Soluble in alcohol, acetic acid, DMSO, ethanol	4
LogP	4.15	2
SMILES	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	2

Endogenous Function and Pharmacological Action

Role in Human Physiology

Chenodeoxycholic acid is one of the two primary bile acids synthesized by the human liver, the other being cholic acid.[4] It is a natural product of cholesterol catabolism, formed through a complex, multi-step enzymatic pathway involving key cytochrome P450 enzymes such as CYP7A1, CYP8B1, and CYP27A1.[5] In its physiological capacity, CDCA functions as a powerful biological surfactant. Its amphipathic structure enables it to form micelles that emulsify dietary lipids, cholesterol, and fat-soluble vitamins within the small intestine, a critical step for their digestion by lipases and subsequent absorption across the intestinal mucosa.[8]

Before secretion from hepatocytes into the bile, CDCA is conjugated with the amino acids taurine or glycine. This process forms bile salts, such as taurochenodeoxycholate and glycochenodeoxycholate, which have a lower pKa than the unconjugated acid.[4] This chemical modification ensures that they remain ionized and functionally effective as detergents in the alkaline environment of the duodenum.

The vast majority of secreted CDCA is efficiently reabsorbed in the terminal ileum and returned to the liver via the portal circulation, a process known as enterohepatic circulation. This recycling mechanism is highly efficient, allowing the body's limited bile acid pool to be used multiple times during a single meal.[8] A small fraction (up to 10%) of CDCA escapes reabsorption and enters the colon. There, it is metabolized by the resident gut microbiota into secondary bile acids. The principal metabolites are lithocholic acid (LCA), formed via dehydroxylation, and ursodeoxycholic acid (UDCA), its  epimer.[1] These microbial metabolites also participate in bile acid signaling and contribute to the overall composition of the circulating bile acid pool.

Pharmacodynamics and Mechanism of Action

The therapeutic effects of exogenous chenodeoxycholic acid are rooted in its ability to modulate the same physiological pathways it regulates as an endogenous signaling molecule. Its actions are complex, involving interactions with multiple nuclear and membrane-bound receptors.

Molecular Targets

The primary molecular target for CDCA is the Farnesoid X Receptor (FXR), a nuclear receptor highly expressed in the liver and intestine.[5] CDCA is the most potent natural agonist for FXR.[4] Upon activation, FXR forms a heterodimer with the Retinoid X Receptor (RXR) and binds to specific DNA response elements, regulating the transcription of a wide array of genes involved in bile acid, lipid, and glucose homeostasis. This receptor is the central node through which CDCA exerts its major metabolic and therapeutic effects.[3]

CDCA also interacts with the G-protein coupled bile acid receptor 1 (GPBAR1, also known as TGR5), a membrane receptor. The nature of this interaction appears complex, with some data suggesting antagonism while other evidence links it to physiological responses like glucagon-like peptide-1 (GLP-1) release.[1] Additionally, CDCA has been identified as a substrate for enzymes like Aldo-keto reductase family 1 member C2 (AKR1C2) and an inhibitor of 5β-reductase (AKR1D1) and 11β-HSD1 dehydrogenase, indicating a broad range of biological activities.[1]

Mechanism in Gallstone Dissolution

The formation of cholesterol gallstones occurs when bile becomes supersaturated with cholesterol, allowing it to precipitate out of solution and form crystals. The therapeutic mechanism of CDCA is to reverse this process by altering the chemical composition of bile to favor cholesterol solubilization.[1]

Administration of oral CDCA expands the body's bile acid pool and enriches it with CDCA. The elevated intrahepatic concentrations of CDCA activate FXR, which in turn initiates a negative feedback loop that suppresses the activity of cholesterol -hydroxylase (CYP7A1), the rate-limiting enzyme in bile acid synthesis.[6] This action reduces the liver's synthesis of both cholesterol and cholic acid.[1] The dual effect of reducing the primary solute (cholesterol) and increasing the concentration of the primary solvent (bile acids) leads to the desaturation of biliary cholesterol. Over a period of months to years, this less saturated bile gradually dissolves existing cholesterol-rich, radiolucent gallstones.[1] The treatment is ineffective for stones that are calcified (radiopaque) or composed primarily of bile pigments.[1]

Mechanism in Cerebrotendinous Xanthomatosis (CTX)

Cerebrotendinous Xanthomatosis is a rare genetic disorder caused by mutations in the CYP27A1 gene, which encodes the mitochondrial enzyme sterol 27-hydroxylase.[4] This enzyme is essential for the normal synthesis of both cholic acid and chenodeoxycholic acid from cholesterol. Its deficiency results in two primary pathological consequences:

1. A profound lack of endogenous CDCA production.
2. The shunting of cholesterol precursors into an alternative metabolic pathway, leading to the massive accumulation of the toxic sterol cholestanol and other atypical bile alcohols (e.g., 23S-pentol) in plasma and tissues, including the brain, tendons, and lenses.[8]

In this context, CDCA functions as a direct replacement therapy. By providing the missing primary bile acid, the treatment restores physiological levels of CDCA within the enterohepatic circulation.[19] This re-establishes the critical negative feedback signaling through FXR on CYP7A1, effectively shutting down the overactive synthesis pathway that generates cholestanol and other toxic metabolites.[12] The therapy corrects the fundamental biochemical abnormality of the disease, leading to a reduction in cholestanol levels and the stabilization or improvement of clinical symptoms.[4]

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

The pharmacokinetic profile of chenodeoxycholic acid is characterized by efficient intestinal absorption and extensive enterohepatic circulation, which confines the majority of the drug to the gastrointestinal tract and liver, minimizing systemic exposure. A summary of key parameters is provided in Table 2.

• Absorption: Following oral administration, CDCA is well absorbed from the small intestine.[1] Peak plasma concentrations () are reached in approximately 3 hours.[19]
• Distribution: CDCA is highly bound to plasma proteins, primarily albumin (~98%).[19] Its distribution is largely restricted to the enterohepatic compartment (liver, biliary tract, intestine). This sequestration results in low systemic serum concentrations despite a relatively high apparent volume of distribution (: 0.36 L/kg), a characteristic feature of substances undergoing extensive enterohepatic recirculation.[15]
• Metabolism: After absorption and transport to the liver, CDCA is efficiently extracted from portal blood and conjugated with glycine or taurine before being secreted into the bile.[1] A therapeutically relevant portion of the daily dose escapes ileal reabsorption and is metabolized by colonic bacteria into the secondary bile acid lithocholic acid (LCA).[1]
• Excretion: Elimination of CDCA is predominantly through the feces.[15] The major bacterial metabolite, LCA, is also primarily excreted in feces. Approximately 20% of LCA is absorbed from the colon, transported to the liver, and detoxified by conversion to poorly absorbed sulfolithocholyl conjugates, which are then excreted.[19] Because of the highly efficient enterohepatic circulation, overall systemic clearance is low (20 L/hr).[15]

The pharmacokinetic behavior of CDCA is inextricably linked to its safety profile. The very process of enterohepatic circulation that makes it an effective therapy for biliary disorders also exposes it to metabolic transformation in the gut. The conversion to lithocholic acid, a more hydrophobic and potentially hepatotoxic compound, is the likely source of the dose-related liver enzyme elevations observed during therapy.[18] The body's detoxification mechanism (sulfation of LCA) can be overwhelmed at higher therapeutic doses, leading to mild hepatic stress. Similarly, the spillover of unabsorbed bile acids into the colon stimulates fluid and electrolyte secretion, directly causing the most common side effect: diarrhea.[4] Therefore, the drug's physiological pathway is also the source of its primary dose-limiting toxicities, creating a therapeutic window that requires careful management through dose titration and clinical monitoring.

Table 2: Summary of Pharmacokinetic (ADME) Parameters

Parameter	Value	Source(s)
Absorption	Well absorbed from the small intestine	1
Peak Plasma Time ()	~3 hours	19
Protein Binding	~98%	19
Volume of Distribution ()	0.36 L/kg	19
Metabolism	Hepatic conjugation (glycine, taurine); colonic bacterial conversion to lithocholic acid	1
Systemic Clearance	20 L/hr	19
Route of Elimination	Primarily feces (~80%)	19

Clinical Efficacy and Therapeutic Applications

The clinical utility of chenodeoxycholic acid has undergone a significant transformation, evolving from a second-line option for a common condition to a first-line, indispensable therapy for a rare genetic disease.

Approved Indication: Radiolucent Gallstone Dissolution

Clinical Evidence and Efficacy Rates

CDCA is indicated for the medical dissolution of cholesterol gallstones in patients who have a functioning gallbladder but for whom elective surgery poses an increased risk due to age or systemic disease.[1] The foundational clinical evidence for this indication comes from large-scale studies conducted in the 1970s and 1980s. The landmark National Cooperative Gallstone Study (NCGS), a double-masked, placebo-controlled trial involving 916 patients, demonstrated that a dose of 750 mg/day resulted in confirmed complete stone dissolution in 13.5% of patients over 24 months, compared to just 0.8% in the placebo group.[21] When considering partial (>) or complete dissolution, the response rate in the high-dose group was 40.8%.[27]

Subsequent uncontrolled trials using higher, weight-based doses of 13 to 16 mg/kg/day reported higher complete dissolution rates, ranging from 28% to 38%.[21] The efficacy of the treatment is highly dependent on the characteristics of the gallstones. The likelihood of successful dissolution is greatest for small stones (less than 15 mm in diameter) and those that are floatable in the gallbladder (indicating a high cholesterol content and low density).[1] For patients with small, floatable stones, complete dissolution rates as high as 42% to 70% have been observed.[21]

Patient Selection and Limitations

The role of CDCA in treating gallstones has become highly specialized and limited. The introduction of laparoscopic cholecystectomy provided a safe, effective, and definitive surgical solution that has become the standard of care, markedly decreasing the need for medical therapy.[18] Furthermore, ursodeoxycholic acid (UDCA), the  epimer of CDCA, was subsequently found to be equally or more effective and significantly better tolerated, with a much lower incidence of diarrhea and hepatotoxicity.[14] As a result, UDCA has largely replaced CDCA as the preferred oral bile acid for gallstone dissolution. A major limitation of medical therapy is the high rate of stone recurrence, which occurs in approximately 50% of patients within five years after treatment is discontinued.[18]

Approved Indication: Cerebrotendinous Xanthomatosis (CTX)

Pathophysiology and Rationale for Treatment

The repurposing of CDCA for Cerebrotendinous Xanthomatosis represents a triumph of translational medicine, where understanding the molecular basis of a disease identified a perfect therapeutic match. As detailed previously, CTX results from a deficiency in sterol 27-hydroxylase, leading to a lack of CDCA and an accumulation of toxic cholestanol.[4] CDCA acts as a direct replacement for the missing bile acid, restoring the crucial FXR-mediated negative feedback on bile acid synthesis and thereby normalizing the aberrant biochemistry.[19] Early diagnosis and initiation of lifelong CDCA therapy are critical, as treatment can halt disease progression, prevent irreversible neurological damage, and in some cases, partially reverse existing symptoms.[12]

Clinical Evidence and Outcomes

The approval of Ctexli by the U.S. FDA for adults with CTX was a landmark event, based on robust evidence from the Phase 3 RESTORE study.[4] This randomized, double-blind, placebo-controlled withdrawal trial demonstrated that treatment with CDCA at a dose of 250 mg three times daily led to a highly statistically significant reduction in key biochemical markers of the disease, including plasma cholestanol and urinary 23S-pentol, compared to placebo.[4] The clinical benefit of CDCA in CTX is further supported by decades of off-label use and several retrospective studies. These studies consistently show that long-term treatment normalizes biochemical parameters and can stabilize or improve neurological function, particularly when therapy is initiated before significant disability has developed.[30]

This dramatic shift in clinical application illustrates the renaissance of CDCA. Initially a therapy for managing a common symptom (gallstones) with a marginal risk-benefit profile, it has been transformed into an essential, disease-modifying agent for a devastating genetic disorder. For a CTX patient, the risks of diarrhea and manageable liver enzyme elevations are highly acceptable when weighed against the benefit of preventing progressive dementia, ataxia, and premature death. This repurposing has not only saved lives but has also reignited scientific interest in CDCA's core mechanism of FXR agonism, paving the way for research into other complex metabolic diseases.

Off-Label and Investigational Uses

The potent biological activities of CDCA, particularly its effects on gut motility and metabolic regulation via FXR, have prompted investigation into several other therapeutic areas.

Chronic Constipation and Irritable Bowel Syndrome with Constipation (IBS-C)

The well-documented side effect of diarrhea during gallstone therapy led to the logical investigation of CDCA as a treatment for constipation.[4] Clinical studies have confirmed that CDCA accelerates colonic transit and improves bowel function in patients with chronic constipation and IBS-C. It has been shown to increase stool frequency, improve stool consistency (making it looser), and increase the ease of stool passage.[33] These effects are attributed to the pro-secretory and prokinetic actions of bile acids in the large intestine.[35]

Cholestatic Liver Diseases

• Primary Biliary Cholangitis (PBC): Although UDCA is the standard of care, CDCA has been used for PBC and is being explored for its potential hepatoprotective and immunomodulatory effects.[1]
• Nonalcoholic Fatty Liver Disease (NAFLD): As a potent natural FXR agonist, CDCA holds promise for treating NAFLD and its more severe form, nonalcoholic steatohepatitis (NASH). FXR activation can modulate lipid metabolism, reduce hepatic fat accumulation (steatosis), and decrease liver inflammation.[13] The development of obeticholic acid, a semi-synthetic and more potent FXR agonist derived from CDCA, specifically for NASH and PBC, validates this therapeutic approach.[37]
• Bile Acid Synthesis Disorders (BASD): In countries where cholic acid is not commercially available, CDCA is used off-label as a treatment for specific BASDs (e.g., HSD3B7 and SRD5B1 deficiencies). By providing a primary bile acid, it restores the negative feedback mechanism and reduces the accumulation of cytotoxic bile acid intermediates that cause cholestatic liver injury.[38]

Other Emerging Research Areas

• Hepatitis C: A combination therapy of CDCA with the fibrate bezafibrate has been tested for the treatment of hepatitis C infection by an Australian biotechnology company.[4]
• Neuroprotection: Preclinical research suggests that CDCA may have neuroprotective properties, potentially through neurotrophic and anti-inflammatory mechanisms, leading to interest in its role in neurodegenerative disorders like Alzheimer's and Parkinson's disease.[13]
• Metabolic Regulation: Given its central role in activating FXR and TGR5, CDCA is a molecule of interest for treating broader metabolic conditions, including obesity, type 2 diabetes, and atherosclerosis.[6] A recent study identified CDCA as a potential biomarker for obesity-induced endothelial dysfunction and its derivative, taurochenodeoxycholic acid (TCDCA), as a potential therapeutic agent.[41]

Dosing, Administration, and Clinical Practice Guidelines

The administration of chenodeoxycholic acid requires careful, indication-specific dosing and vigilant patient monitoring to maximize efficacy and mitigate risks.

Formulations and Strengths

Chenodeoxycholic acid is available for oral administration as 250 mg tablets.[18] The commercially available products include Chenodal and Ctexli.[1] For pediatric patients or individuals who are unable to swallow tablets, the contents of the capsules can be opened and mixed with an 8.4% sodium bicarbonate solution to create an oral liquid suspension for administration.[42]

Dosing Regimens

Dosing strategies for CDCA differ significantly based on the therapeutic indication, as summarized in Table 3.

• Radiolucent Gallstone Dissolution (Chenodal): The recommended dosage is based on body weight, ranging from 13 to 16 mg/kg/day, administered in two divided doses, typically in the morning and evening.[18] To improve tolerability, particularly to minimize diarrhea, treatment should be initiated at a low dose of 250 mg twice daily for the first two weeks. The dose is then gradually increased by 250 mg per day at weekly intervals until the target or maximum tolerated dose is reached.[19] Doses below 10 mg/kg/day are generally ineffective and are not recommended.[21] An off-label combination approach with ursodeoxycholic acid may involve a lower CDCA dose of 5-7.5 mg/kg/day.[19]
• Cerebrotendinous Xanthomatosis (CTX) (Ctexli): The standard approved dosage for adults is a fixed dose of 250 mg taken orally three times per day.[4] For pediatric patients, a weight-based dose of 15 mg/kg/day divided into three doses has been used in clinical practice.[12]

Table 3: Dosing Regimens for Approved Indications

Indication	Brand Name(s)	Recommended Dosage	Administration Schedule	Key Clinical Notes
Radiolucent Gallstone Dissolution	Chenodal	13–16 mg/kg/day	Two divided doses (morning and evening)	Start at 250 mg BID and titrate up weekly to improve gastrointestinal tolerance. A low cholesterol diet is recommended. Treatment duration up to 24 months. 18
Cerebrotendinous Xanthomatosis (CTX)	Ctexli, Chenodeoxycholic acid Leadiant	Adults: 250 mg TID Children: 15 mg/kg/day	Three times daily (TID)	Lifelong replacement therapy. Early initiation is crucial to prevent disease progression. 4

Monitoring and Patient Management

Systematic monitoring is a critical component of CDCA therapy due to its potential for hepatotoxicity.

• Liver Function Monitoring: Baseline liver function tests, including serum aminotransferases (ALT, AST) and total bilirubin, must be obtained before initiating therapy for any indication.[19] These tests should be monitored periodically throughout treatment, typically on a yearly basis or more frequently as clinically indicated.[19]
• Dose Adjustment for Hepatotoxicity: If liver transaminase levels rise to greater than 3 times the upper limit of normal (ULN) or if total bilirubin exceeds 2 times ULN, treatment should be interrupted until the values return to baseline.[19] For persistent or recurrent liver test abnormalities, discontinuation of the drug should be considered.[19]
• Dietary Considerations: For patients undergoing treatment for gallstone dissolution, adherence to a low-cholesterol diet is recommended to complement the drug's mechanism of action and may potentially reduce the minimum effective dose required.[10]

Safety Profile and Risk Management

The therapeutic use of chenodeoxycholic acid is limited by a distinct safety profile, dominated by gastrointestinal side effects and the potential for liver injury.

Adverse Drug Reactions

• Common (>10%): The most frequently reported adverse effect is diarrhea, which is dose-related and occurs in a significant portion of patients, with one report citing an incidence of 36%.[4] It is often manageable with dose reduction.[21] Other common side effects, particularly noted in the treatment of CTX, include headache (21%), abdominal pain (14%), constipation (14%), hypertension (14%), muscular weakness (14%), and upper respiratory tract infection (14%).[4]
• Less Common: A notable adverse effect is an increase in serum transaminase levels, which can occur in up to 30% of patients during gallstone therapy.[18] These elevations are typically mild, transient, and reversible upon dose reduction or discontinuation.[18] An increase in serum cholesterol levels, particularly low-density lipoprotein (LDL) cholesterol, has also been observed.[25]
• Rare: Less frequent gastrointestinal effects include nausea, vomiting, dyspepsia, and flatulence.[18] Post-marketing reports have included hypersensitivity reactions such as rash, pruritus, urticaria, and facial swelling.[19]

Warnings, Precautions, and Contraindications

• Black Box Warning: The prescribing information for Chenodal, the brand indicated for gallstone dissolution, includes a black box warning regarding the potential for hepatotoxicity. The warning emphasizes that the drug is not an appropriate treatment for many patients with gallstones and that its use must be accompanied by systematic monitoring of liver function.[18]
• Hepatotoxicity: This is the most significant safety concern. While dose-related, reversible elevations in liver enzymes are relatively common, rare instances of clinically apparent liver injury with jaundice have been reported.[18] The drug should be used with extreme caution, if at all, in patients with pre-existing liver disease or bile duct abnormalities.[4]
• Contraindications:
• For gallstone dissolution (Chenodal): The drug is contraindicated in patients with known hepatocyte dysfunction or bile duct abnormalities (e.g., intrahepatic cholestasis, primary biliary cirrhosis, sclerosing cholangitis), gallstone complications requiring surgery (e.g., biliary colic, cholecystitis), or inflammatory bowel disease.[19]
• For CTX (Ctexli): No contraindications are listed in the prescribing information.[19]
• Pregnancy: For the gallstone indication, CDCA is classified as Pregnancy Category X. Weight loss during pregnancy offers no benefit and may result in fetal harm.[49]
• Potential Carcinogenicity: Some epidemiological evidence has suggested a possible association between higher fecal concentrations of bile acids, including CDCA, and an increased risk of colorectal cancer. However, this link is considered weak and has not been definitively established.[4]

Significant Drug Interactions

The efficacy and safety of CDCA can be altered by concomitant medications. Clinically significant interactions are summarized in Table 4. The most important interactions involve agents that interfere with its absorption or counteract its therapeutic mechanism.

Table 4: Clinically Significant Drug-Drug Interactions

Interacting Drug/Class	Mechanism of Interaction	Clinical Consequence	Management Recommendation	Source(s)
Bile Acid Sequestrants (e.g., cholestyramine, colestipol)	Binding of CDCA in the GI tract	Decreased absorption and efficacy of CDCA	Separate administration by at least 5 hours. Monitor for reduced therapeutic effect.	10
Aluminum-Containing Antacids	Binding of CDCA in the GI tract	Decreased absorption and efficacy of CDCA	Avoid co-administration. If necessary, separate doses by several hours.	1
Estrogens / Oral Contraceptives	Increased biliary cholesterol secretion	Antagonism of the therapeutic effect for gallstone dissolution	Monitor for decreased efficacy. Consider alternative therapies if possible.	10
Fibrates (e.g., bezafibrate, fenofibrate)	Increased biliary cholesterol secretion	Antagonism of the therapeutic effect for gallstone dissolution	Monitor for decreased efficacy.	50
Warfarin	Potential alteration of pharmacodynamics due to CDCA-induced hepatotoxicity	Increased risk of bleeding (prolonged prothrombin time)	Avoid or modify warfarin dose. If co-administration is necessary, monitor prothrombin time closely.	19
Cyclosporine	Increased intestinal absorption of cyclosporine	Potential for cyclosporine toxicity	Monitor cyclosporine levels and adjust dose as needed.	46

Regulatory Landscape and Approval History

The regulatory history of chenodeoxycholic acid is a compelling narrative that reflects its clinical evolution and highlights the complex interplay between drug development, rare diseases, and pharmaceutical economics.

United States (FDA)

• Gallstone Dissolution: Chenodiol was first approved by the U.S. Food and Drug Administration (FDA) in 1983 under the brand name Chenodal for the treatment of radiolucent gallstones in a select patient population.[7]
• Cerebrotendinous Xanthomatosis (CTX): Recognizing the unmet need for CTX treatment, the FDA granted CDCA an Orphan Drug designation for this indication on February 12, 2007.[52] After decades of off-label use and the successful completion of the pivotal RESTORE trial, the FDA granted full approval to Ctexli (chenodiol) tablets on February 21, 2025, for the treatment of adults with CTX.[4] This approval, granted to Mirum Pharmaceuticals, was expedited through the FDA's priority review and fast track programs, marking it as the first-ever approved therapy for CTX in the United States.[4]

European Union (EMA)

The European Medicines Agency (EMA) also recognized the critical need for an approved CTX therapy. On December 16, 2014, CDCA received an orphan designation for the treatment of inborn errors of primary bile acid synthesis.[42] A marketing authorization was subsequently granted on April 10, 2017, for "Chenodeoxycholic acid sigma-tau," which was later renamed "Chenodeoxycholic acid Leadiant".[42]

This approval was granted under 'exceptional circumstances,' a regulatory pathway used when the rarity of a condition makes it impossible to collect a full set of efficacy and safety data through conventional clinical trials. This status requires the marketing authorization holder to conduct ongoing monitoring and provide updated data to the EMA annually.[42]

Australia (TGA)

The regulatory status of chenodeoxycholic acid in Australia is less clear than in the US and EU. A specific product containing CDCA as the active ingredient does not appear to be currently registered on the Australian Register of Therapeutic Goods (ARTG).[54] However, related bile acids are regulated and available. Ursodeoxycholic acid is a Schedule 4 (Prescription Only) medicine approved for treating chronic cholestatic liver diseases.[55] A 2018 scheduling decision from the Therapeutic Goods Administration (TGA) noted that chenodeoxycholic acid is included in Schedule 4 of the Poisons Standard, meaning a prescription would be required for its supply, but this does not confirm the availability of a TGA-approved marketed product.[56] An Australian company has explored CDCA in a clinical trial context, but this does not equate to a marketing authorization.[4]

The regulatory journey of CDCA provides a powerful case study on the role of orphan drug legislation. These regulations were designed to incentivize the development of drugs for rare diseases that would otherwise be commercially non-viable. In the case of CDCA for CTX, the legislation worked as intended, prompting a company to conduct the formal studies necessary to gain regulatory approval for a life-saving therapy.[24] However, this process also created an unintended consequence. After securing market exclusivity through the orphan drug designation, the manufacturer, Leadiant, drastically increased the price of what had been an inexpensive, off-label medication. This action led to accusations of price gouging and resulted in significant fines from European competition authorities.[57] This history demonstrates that while orphan drug laws can successfully drive innovation for rare diseases, they can also create market failures that lead to profound ethical and economic challenges regarding drug access and affordability.

Concluding Analysis and Future Directions

Chenodeoxycholic acid stands as a remarkable example of a molecule whose clinical and scientific importance has been rediscovered and redefined over time. Its trajectory from a modest, second-line therapy for gallstones to an indispensable, first-in-class treatment for the devastating genetic disorder Cerebrotendinous Xanthomatosis is a testament to the power of mechanistic and translational research. The elucidation of its role as the primary endogenous ligand for the Farnesoid X Receptor has not only explained its therapeutic effects but has also positioned it as a key tool for understanding a central hub of metabolic regulation.

The story of CDCA is one of profound contrasts. It is both a natural, essential physiological compound and a potent therapeutic agent with a narrow therapeutic index. Its pharmacokinetics, dominated by enterohepatic circulation, are both the key to its efficacy in biliary disease and the direct cause of its dose-limiting toxicities. Its regulatory history showcases both the successes of orphan drug legislation in bringing treatments to rare disease populations and the potential for market failures that can threaten patient access through exorbitant pricing.

Looking forward, the therapeutic potential of CDCA and its underlying mechanisms is far from exhausted. The validation of FXR as a druggable target by CDCA has spurred the development of novel, more potent synthetic agonists for a range of highly prevalent conditions. Ongoing research continues to explore the utility of CDCA itself in:

• Gastrointestinal Motility Disorders: Its prokinetic effects offer a potential non-systemic treatment for chronic constipation and IBS-C.
• Metabolic and Liver Diseases: Its ability to modulate lipid and glucose metabolism makes it a continued subject of interest for NAFLD, type 2 diabetes, and other components of the metabolic syndrome.
• Neuroprotection: Emerging preclinical data on its anti-inflammatory and neurotrophic effects may open new avenues for investigation in neurodegenerative diseases.

In conclusion, chenodeoxycholic acid has transitioned from being viewed as a simple digestive aid to being recognized as a critical signaling molecule and a versatile therapeutic platform. Its journey underscores a vital principle in pharmacology: a deep understanding of a drug's fundamental mechanism of action can unlock new and profound therapeutic applications, transforming a nearly obsolete compound into a life-saving medicine and a beacon for future drug discovery.

Works cited

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