Chenodiol

Chenodiol is a Gallstone Solubilizing Agents.

Chenodiol is used in the treatment of Gallstone dissolution and Cerebrotendinous xanthomatosis

Chenodiol is Rapid and almost completely absorbed in proximal small intestine

The Volume of distribution is about 1600 L and Converted hepatically to taurine and glycine conjugates and secreted in bile; extensive first-pass hepatic clearance; undergoes enterohepatic circulation; further metabolized in colon by bacteria to lithocholic acid; small portion of lithocholate is absorbed and converted to sulfolithocholyl conjugates in the liver and get excreted through Feces (~80%, as lithocholate)

The Tmax of Chenodiol was found to be about approximately 2-6 hours.

The Cmax of chenodiol ranges from 22 to 45 µg/mL.

Chenodiol shows common side effects like Diarrhoea, hepatotoxicity, colon cancer, gallstone recurrence.

Chenodiol is available in Tablets

Chenodiol is available in India, Germany, Canada, France, USA

Chenodiol (chenodeoxycholic acid) is a naturally occurring human bile acid, normally constituting one-third of the total bile acid pool. In patients with cholesterol gallstones, chenodiol is believed to suppress hepatic synthesis of cholesterol and cholic acid, and inhibit biliary cholesterol secretion, which leads to increased production of cholesterol unsaturated bile thereby allowing for dissolution of gallstones.

Chenodiol is available in the form of Tablet.

Chenodeoxycholic acid is a naturally occurring human bile acid. It suppresses the hepatic synthesis of both cholesterol and cholic acid, resulting in biliary cholesterol desaturation and gradual dissolution of radiolucent cholesterol gallstones. It does not exhibit any effect on radiopaque gallstones or radiolucent bile pigment stones.

Chenodiol is approved for use in the following clinical indications

Gallstone dissolution: Dissolution of radiolucent cholesterol gallstones in select patients as an alternative to surgery.

Limitations of use: Will not dissolve calcified (radiopaque) or radiolucent bile pigment stones.

Although not approved there have been certain off labelled uses documented for Chenodiol which includes:

Cerebrotendinous xanthomatosis

Cerebrotendinous xanthomatosis (off-label use): Oral: 250 mg 3 times daily for at least 1 year

Gallstone dissolution (monotherapy): Oral: Initial: 250 mg twice daily for 2 weeks, then increase dose by 250 mg/day each week until the recommended maintenance dose or maximum tolerated dose is achieved; maintenance: 13 to 16 mg/kg/day in 2 divided doses. Note: Dosages <10 mg/kg are usually ineffective and may increase the risk of cholecystectomy. If diarrhea occurs, temporarily decrease dose; once symptoms resolve, attempt to reinstate the previous dose. Discontinue treatment if there is no response by 18 months; safe use beyond 24 months has not been established.

Gallstone dissolution (combination therapy; off-label dose): Oral: 5 to 7.5 mg/kg/day once daily at bedtime, in combination with ursodeoxycholic acid, with or without adjuvant lithotripsy.

Chenodiol is available in the dosage strength of 250 mg

Chenodiol is available in the form of Tablets.

Dosage Adjustment in Hepatic impairment Patient

• Preexisting hepatic impairment: There are no dosage adjustments provided in the manufacturer’s labeling; avoid use in patients with preexisting hepatic impairment. Contraindicated for use in presence of known hepatocyte dysfunction or bile duct abnormalities.
• Hepatotoxicity during treatment:
• Aminotransferase level 1.5 to 3 times ULN persisting for >3 to 6 months: Temporarily withhold treatment; resume when aminotransferases levels return to normal.
• Aminotransferase level >3 times ULN: Discontinue treatment immediately.

Dosage Adjustment for Pediatric Patients

• Cerebrotendinous xanthomatosis: Limited data available: Infants, Children, and Adolescents: Oral: Usual dose: 10 to 15 mg/kg/day divided 1 to 3 times daily; maximum daily dose: 750 mg/day; in infants and young children, a lower dose of 5 mg/kg/day in 3 divided doses
• Gallstone dissolution: Limited data available; not routinely used for cholelithiasis in pediatric patients; use has been replaced by other treatments: Children ≥12 years and Adolescents: Oral: 15 mg/kg/day divided 3 times daily with meals; dosing based on reported experience in three obese pediatric patients (age range: 12 to 13 years); Note: Not first-line therapy due to frequent side effects

• Inborn errors of bile acid biosynthesis; steroid dehydrogenase or reductase deficiencies (susceptible) : Very limited data available: Note: Due to the rarity of the disease states, data is limited to small case series and case reports. Adjust dose based upon targeted bile acid or biosynthesis intermediate compound concentrations. Combination therapy with ursodeoxycholic acid (ursodiol) dependent on specific deficiency, and phenotypic presentation of syndrome. Infants, Children, and Adolescents: Oral: Usual initial range: 5 to 10 mg/kg/day divided once or twice daily; higher initial doses of 11 to 18 mg/kg/day have also been reported; a maintenance dose of 5 mg/kg/day was the most frequently reported and initiated once targeted bile acid normalized or stabilized (depending upon the syndrome).

Take after eating and with a full glass of water to decrease gastric upset.

Chenodiol is contraindicated in patients with:

Known hepatocyte dysfunction or bile ductal abnormalities (eg, intrahepatic cholestasis, primary biliary cirrhosis, sclerosing cholangitis); gallbladder confirmed as nonvisualizing after two consecutive single doses of dye; radiopaque stones; gallstone complications or compelling reasons for gallbladder surgery (eg, unremitting acute cholecystitis, cholangitis, biliary obstruction, gallstone pancreatitis, biliary gastrointestinal fistula); use in pregnancy or in patients who can become pregnant.

Concerns related to adverse effects:

• Diarrhea: Dose-related diarrhea commonly occurs (up to 40% of patients); may occur at any time, but is most common during treatment initiation. Diarrhea is usually mild and does not interfere with therapy; however, diarrhea may be severe and a temporary dosage reduction or discontinuation may be required. Antidiarrheal agents may be of benefit in some patients.

• Hepatotoxicity: Drug-induced liver toxicity may occur (dose-related); close monitoring of serum aminotransferase levels recommended during therapy. Aminotransferase elevations >3 times ULN have been reported; prompt discontinuation of therapy recommended. Transaminase levels usually return to normal after chenodiol is withheld. Temporarily withhold therapy for transient transaminase elevations of 1.5 to 3 times ULN. Biochemical and histologic chronic active hepatitis has been reported (rare case reports), although a causal relationship to chenodiol could not be determined.

Disease-related concerns:

• Colon cancer: Epidemiologic studies have suggested that bile acids may increase the risk of colon cancer. Evidence is weak and conflicting; however, a potential link between bile acids and colon cancer cannot be ruled out.

• Hepatic impairment: Avoid use in patients with preexisting hepatic impairment or elevated liver enzymes; use contraindicated in patients with known hepatocyte dysfunction or bile ductal abnormalities.

Chenodiol may cause liver problems, and using it with substantial quantities of ethanol may increase that risk.

Pregnancy Category X

There are no known food interactions with Chenodiol . However, it is recommended to avoid drinking alcohol while taking Chenodiol , as it can increase the risk of drowsiness and dizziness.

• Common Adverse effects:

Diarrhea, hepatotoxicity, colon cancer, gallstone recurrence.

• Less Common Adverse effects:

Increased serum transaminases, increased LDL and total serum cholesterol.

• Rare Adverse effects

Nausea, vomiting, biliary colic, abdominal cramps, abdominal pain, anorexia, constipation, dyspepsia, flatulence.

• Aluminum Hydroxide: May decrease the serum concentration of Chenodiol. Risk C: Monitor therapy

• Bile Acid Sequestrants: May decrease the serum concentration of Chenodiol. Management: Administration of chenodiol 5 hours or more after bile acid sequestrants may reduce the magnitude of this interaction. Monitor for decreased therapeutic effects of chenodiol in patients receiving bile acid sequestrants. Risk D: Consider therapy modification

• Estrogen Derivatives: May diminish the therapeutic effect of Chenodiol. Risk C: Monitor therapy

• Vitamin K Antagonists (eg, warfarin): Chenodiol may enhance the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy

The common side effects of Chenodiol include the following :

Diarrhea, hepatotoxicity, colon cancer, gallstone recurrence.

Pharmacodynamic

• Chenodiol (chenodeoxycholic acid) is a naturally occurring human bile acid, normally constituting one-third of the total bile acid pool. In patients with cholesterol gallstones, chenodiol is believed to suppress hepatic synthesis of cholesterol and cholic acid, and inhibit biliary cholesterol secretion, which leads to increased production of cholesterol unsaturated bile thereby allowing for dissolution of gallstones.

Pharmacokinetics

● Absorption: Rapid, almost completely absorbed in proximal small intestine

● Distribution: V_d: ~1600 L

● Metabolism: Converted hepatically to taurine and glycine conjugates and secreted in bile; extensive first-pass hepatic clearance; undergoes enterohepatic circulation; further metabolized in colon by bacteria to lithocholic acid; small portion of lithocholate is absorbed and converted to sulfolithocholyl conjugates in the liver

● Excretion: Feces (~80%, as lithocholate)

1. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1364710/
2. https://reference.medscape.com/drug/colestid-Chenodiol -342452
3. https://go.drugbank.com/drugs/DB00375
4. https://www.sciencedirect.com/topics/medicine-and-dentistry/Chenodiol
5. https://europepmc.org/article/med/6988203