Gallstone solubilizing agents

Generic and Brand Names

• Ursodeoxycholic acid (ursodiol) — Actigall, Urso/Ursofalk (capsules/tablets), Ursodiol (generics)

• Chenodeoxycholic acid (chenodiol) — Chenodal

• Contact dissolution solvents (specialist use) — Methyl tert-butyl ether (MTBE) (intracystic); Mono-octanoin (intra-ductal, legacy)

Class

• Bile acid–based oral dissolution therapy for radiolucent cholesterol gallstones

• Contact organic solvents for direct chemical dissolution (rare, interventional)

Target Stone Profile & Patient Selection

• Cholesterol, radiolucent, non-calcified stones (≤10–15 mm; “floating” stones respond best)

• Functioning gallbladder with patent cystic duct (opacifies on imaging; ejection fraction adequate)

• Asymptomatic or mildly symptomatic patients declining/unsuitable for cholecystectomy

• Pigment or calcified stones: not responsive to oral bile acids

• Common bile duct (CBD) stones: ERCP is standard; chemical solvents reserved for retained or refractory stones

Mechanism of Action

• Ursodiol: Hydrophilic bile acid → reduces biliary cholesterol saturation (↓ hepatic secretion, micellar solubilization) → gradual cholesterol crystal/stone dissolution; improves bile flow; cytoprotective to cholangiocytes

• Chenodiol: Primary bile acid → suppresses hepatic cholesterol synthesis (↓ HMG-CoA reductase activity) and biliary cholesterol secretion → dissolves cholesterol stones; more diarrheagenic/hepatotoxic than ursodiol

• MTBE/mono-octanoin: Organic solvents that directly dissolve cholesterol on contact (rapid, localized)

Indications

• Oral dissolution (ursodiol, chenodiol)

  • Radiolucent cholesterol gallstones in patients with a functioning gallbladder who are poor surgical candidates or decline surgery

  • Biliary sludge/microlithiasis with biliary-type pain or pancreatitis risk (ursodiol)

  • Prophylaxis of gallstones during rapid weight loss/bariatric surgery (ursodiol)

• Contact dissolution (MTBE/mono-octanoin)

  • Refractory cholesterol stones when surgery/ERCP fail or are contraindicated (specialist centers only)

Dosage and Administration

• Ursodiol (oral)

  • Gallstone dissolution: 8–10 mg/kg/day PO in 2–3 divided doses (some protocols up to 12–15 mg/kg/day)

  • Bariatric/rapid-weight-loss prophylaxis: fixed 300 mg BID (common regimen) for 6 months

  • Duration: typically 6–24 months; continue 3 months after imaging-confirmed dissolution to reduce early recurrence

• Chenodiol (oral)

  • Target 12–16 mg/kg/day PO in 2 divided doses; start 250 mg BID and titrate at ≥1–2-week intervals to tolerability

  • Limit dose if diarrhea or LFTs rise; treatment duration similar to ursodiol

• MTBE (intracystic)

  • Percutaneous transhepatic or transpapillary catheter instillation into the gallbladder; dissolution within hours–days; requires continuous monitoring and anesthesia support

• Mono-octanoin (intra-ductal)

  • Slow infusion via biliary catheter for retained CBD stones post-ERCP; hours to days; now rarely used

Monitoring

• Baseline: ultrasound, LFTs (ALT/AST/ALP/bilirubin), pregnancy status (if applicable)

• On therapy:

  • Ultrasound every 6 months to document size reduction/dissolution

  • LFTs: at 6–12 weeks then q3–6 months (monthly early if on chenodiol)

  • Symptoms: biliary colic, diarrhea, pruritus; adherence and weight-loss context

• Stop rules: no size reduction by 6–12 months; calcification develops; LFTs persistently >3× ULN; biliary complications arise

Contraindications

• Calcified or radiopaque stones, porcelain gallbladder

• Nonfunctioning gallbladder or cystic duct obstruction

• Acute cholecystitis, cholangitis, biliary obstruction

• Pregnancy: avoid chenodiol (fetotoxicity in animals); use ursodiol only if potential benefit outweighs risk

• Active chronic liver disease with decompensation (relative/agent-specific)

• Known hypersensitivity to bile acids or solvent agents

Precautions

• Stone recurrence after successful dissolution is common (≈30–50% within 5 years); consider low-dose continuation in high-risk settings or definitive surgery if symptoms recur

• Body habitus & stone burden: multiple or large stones respond poorly

• Estrogen therapy, pregnancy, fibrates may increase biliary cholesterol saturation and antagonize efficacy

• Contact solvents: chemical cholecystitis, mucosal injury, hemolysis, arrhythmias (vapor exposure); restrict to expert centers

Adverse Effects

• Ursodiol: generally well tolerated; diarrhea, dyspepsia, nausea, pruritus, mild LFT elevations, rare alopecia/rash

• Chenodiol: dose-related diarrhea, transaminase elevations/hepatitis, abdominal pain, hypercholesterolemia; menstrual irregularities

• MTBE/mono-octanoin: severe RUQ pain, chemical cholecystitis, nausea/vomiting, hemolysis; rare cardiac arrhythmias (MTBE vapors)

Drug Interactions

• ↓ Absorption of bile acids: cholestyramine/colesevelam/colestipol, aluminum-containing antacids; separate by ≥2–4 hours

• Reduced effectiveness: estrogens/oral contraceptives, fibrates (↑ bile cholesterol saturation)

• Cyclosporine: ursodiol may increase cyclosporine absorption; monitor levels and adjust dose

• Warfarin: no direct interaction expected; monitor INR if diet/weight change significantly

Overdose

• Presentation: primarily diarrhea and abdominal cramps; with chenodiol, possible marked LFT elevations

• Management: stop drug, supportive care, correct fluids/electrolytes; monitor LFTs until normalization

Patient Counselling

• Therapy is slow; expect months before stones shrink; strict adherence is crucial

• Take doses with food to improve tolerability

• Report worsening RUQ pain, fever, jaundice, persistent diarrhea, or dark urine/pale stools

• Pregnancy planning: discuss risks (avoid chenodiol)

• During rapid weight loss/bariatric programs, ursodiol prophylaxis reduces new gallstone formation

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Comparison Table 1 — Oral Bile Acids for Cholesterol Gallstones

Feature	Ursodiol (UDCA)	Chenodiol (CDCA)
Primary action	↓ Biliary cholesterol saturation; cytoprotective	↓ Hepatic cholesterol synthesis & secretion
Best candidates	Small, radiolucent stones; functioning GB; sludge/microlithiasis; bariatric prophylaxis	Similar selection, but reserve if UDCA not suitable
Typical dose	8–10 mg/kg/day (up to 12–15 mg/kg) divided	12–16 mg/kg/day divided; slow uptitration
Tolerability	Favorable; mild GI effects	Less well tolerated; diarrhea, hepatotoxicity risk
LFT monitoring	Baseline, then q3–6 mo	Baseline, 6–12 wk, then q1–3 mo (closer early)
Time to response	6–24 mo	6–24 mo
Dissolution success	Highest when stones ≤10 mm and few in number	Similar when tolerated and fully dosed
Recurrence	30–50% within years after cessation	30–50% similar
Pregnancy	Generally avoid unless benefit > risk	Avoid (fetotoxicity in animals)

Comparison Table 2 — Dissolution vs Procedural Strategies

Scenario	Oral UDCA/CDCA	Contact solvent (MTBE/mono-octanoin)	ESWL + UDCA	ERCP	Laparoscopic cholecystectomy
Target	GB cholesterol stones (radiolucent)	GB/CBD cholesterol stones refractory to standard care	Selected GB cholesterol stones	CBD stones	All symptomatic GB stones
Onset of effect	Months	Hours–days	Weeks–months (after fragmentation)	Immediate stone clearance	Immediate definitive removal
Success factors	Small, few, non-calcified, functioning GB	Catheter access, solvent tolerance	Stone size/number; availability	Duct anatomy, stone size	Surgical fitness
Recurrence	Common (30–50%)	Possible if GB retained	Common if GB retained	Possible if gallbladder retained	Minimal (GB removed)
Adverse risks	Mild GI, LFT changes	Chemical cholecystitis, hemolysis, arrhythmias	Pain, hemobilia (rare)	Pancreatitis, bleeding, perforation	Surgical/GA risks, bile duct injury
Role today	Niche (selected patients/ prophylaxis)	Rare (salvage only)	Rare	Standard for CBD stones	Standard of care for symptomatic GB stones

Comparison Table 3 — Ursodiol Prophylaxis During Rapid Weight Loss

Setting	Typical Regimen	Expected Benefit	Notes
Bariatric surgery (e.g., sleeve, RYGB)	Ursodiol 300 mg BID for 6 months	Reduces new gallstone formation during rapid weight loss	Consider longer in persistent rapid weight loss
Very-low-calorie diets	Ursodiol 300 mg BID while on VLCD	Decreases sludge/stone formation	Reassess once weight stabilizes

Practical Positioning

• Use ursodiol as the first-choice oral agent for carefully selected patients with small, non-calcified cholesterol stones and a functioning gallbladder, or for stone prophylaxis during rapid weight loss.

• Reserve chenodiol for cases where ursodiol is unsuitable and close LFT and symptom monitoring is feasible.

• Prefer ERCP for ductal stones and laparoscopic cholecystectomy for most symptomatic gallbladder disease; chemical solvents are salvage options in expert hands only.