Lithocholate metabolism during chemotherapy for gallstone dissolution. 2. Absorption and sulphation

Area of Science:

• Hepatology
• Bile Acid Metabolism
• Pharmacology

Background:

• Chenodeoxycholic acid (CDCA) is used for gallstone dissolution.
• CDCA administration increases the body's lithocholic acid (LCA) pool.
• LCA can be hepatotoxic, necessitating investigation into its metabolic fate during CDCA therapy.

Purpose of the Study:

• To quantify LCA input and pool size in patients undergoing CDCA therapy versus healthy controls.
• To determine the extent of LCA sulfation in bile during CDCA therapy.
• To elucidate the role of LCA sulfation in preventing CDCA-induced hepatotoxicity.

Main Methods:

• Isotope dilution and stochastic analysis (Stewart-Hamilton equation) for LCA input and pool size.
• Measurement of radioactivity in bile after intravenous administration of labeled LCA, lithocholylglycine, and lithocholyltaurine.
• Analysis of the chemical form of radioactivity in bile to assess sulfation extent.

Main Results:

• Gallstone patients on CDCA showed 4-5 times higher LCA input and pool size than controls.
• Approximately one-fifth of newly formed LCA was absorbed in both groups.
• Injected LCA was predominantly excreted as sulfated conjugates (50-60%) in bile.
• Glycine conjugates of LCA were preferentially sulfated compared to taurine conjugates.

Conclusions:

• CDCA therapy leads to increased LCA absorption and pool size.
• Effective sulfation of LCA, especially glycine conjugates, occurs in patients on CDCA.
• This efficient sulfation mechanism likely prevents LCA-induced hepatotoxicity in humans.
• Findings support the safety profile of CDCA in gallstone dissolution therapy.