Metabolism-mediated herb-drug interaction between milk thistle and resmetirom in MCD diet-induced metabolic dysfunction-associated steatohepatitis rat model.

Resmetirom is a liver-directed thyroid hormone receptor-β agonist for metabolic dysfunction-associated steatohepatitis, whereas milk thistle is widely used as a hepatoprotective supplement. This study evaluated whether milk thistle supplement coadministration alters resmetirom metabolism, systemic exposure, and pharmacological response. A validated LC-MS/MS method was used to quantify resmetirom in rat plasma and microsomal samples. Male Sprague-Dawley rats with a methionine and choline-deficient diet-induced metabolic dysfunction-associated steatohepatitis (MASH) received vehicle, resmetirom (8 mg/kg), milk thistle supplement (100 mg/kg total silybin A + B equivalent), or their combination for 8 days. Milk thistle increased resmetirom Cmax by 17 %, AUC0-t by 37 %, and AUC0-∞ by 32 %, while reducing apparent oral clearance by 25 %. In rat liver microsomes, milk thistle supplement extract (50 µM total silybin A + B equivalent) decreased the resmetirom elimination-rate constant from 0.0021 to 0.0002 min-1, prolonged microsomal half-life from 330.84 to 3914.31 min, and reduced intrinsic clearance from 3.88 to 0.39 µL/min/mg protein. The combination was associated with greater improvements in liver enzymes, bilirubin, lipid parameters, relative liver weight, body-weight recovery, and hepatic histology than either monotherapy. These findings provide preclinical evidence of a metabolism-mediated milk thistle-resmetirom interaction that increases resmetirom exposure and is accompanied by an enhanced pharmacodynamic response in rats.