Integrated pharmacokinetic properties and tissue distribution of Corydalis saxicola Bunting total alkaloids in HFHCD-induced mice: Implications for pharmacokinetic variability in MASH treatment

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a typical chronic liver disease characterized by excessive lipid accumulation in the liver. It can develop to the severe stage, Metabolic dysfunction-associated steatohepatitis (MASH), which is accompanied by inflammation and fibrosis. Corydalis saxicola Bunting total alkaloids (CSBTA) exert therapeutic potential to fight against MASLD/MASH progression. The present study was designed to evaluate the pharmacokinetic (PK) variability of dehydrocavidine, palmatine and berberine, the major bioactive components of CSBTA, in normal or high-fat and high-cholesterol diet (HFHCD)-induced mice after single or multiple intragastric administration. Contents of the three alkaloids in mice plasma, tissue and cells were detected by ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) and the expressions of drug metabolizing enzymes/transporters were measured. The pathological status definitely influenced the PK process of the three representative ingredients in different degrees, including elevated systemic exposure, liver distribution and intracellular accumulation in hepatocytes. While multiple dosing of CSBTA further raised the amounts in plasma and liver of MASH mice, especially for dehydrocavidine. Based on the transporting (transfected-HEK293 cells and Caco-2 cells model) and metabolism (liver microsomes) assay, the PK variability of the three representative alkaloids was integrally associated with the expression perturbations of Cyp450s, Oatp1b2 and P-gp. From the perspective of PK, long-term CSBTA treatment resulted in higher systemic exposures and liver distribution in MASH mice through modulating Cyp450s and specific transporters via PXR. These results provided valuable guidance for rationalizing the clinical dosage regimen in MASLD/MASH treatment.