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

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

  • Biomed Pharmacother. 2025 Oct 21:192:118665. doi: 10.1016/j.biopha.2025.118665.
Qiushuang Sun 1,  Huan Chen 2,  Qianqian Lin 3,  Yanyi Wu 3,  Yuanyuan Lei 3,  Xianhai Luo 3,  Ning Li 4,  Luzhou Xu 5,  Sufeng Zhou 6,  Jun Cheng 7,  Fang Huang 8,  Zhixia Qiu 9
Affiliations

Affiliations

  • 1 Department of Pharmacology of Chinese Materia Medica, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 211198, China; School of Health, Jiangsu Vocational Institute of Commerce, Nanjing 211168, China.
  • 2 Department of Pharmacology of Chinese Materia Medica, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 211198, China.
  • 3 Department of Pharmacology, School of Pharmacy, China Pharmaceutical University, Nanjing 211198, China.
  • 4 National Experimental Teaching Demonstration Center of Pharmacy, School of Pharmacy, China Pharmaceutical University, Nanjing 211198, China.
  • 5 Gastroenterology Department, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210004, China.
  • 6 Phase I Clinical Trial Unit, the First Affiliated Hospital with Nanjing Medical University, Nanjing 210029, China.
  • 7 Nanjing Zhongshan Pharmaceutical Co, Ltd., Nanjing 210046, China. Electronic address: 316609549@qq.com.
  • 8 Department of Pharmacology of Chinese Materia Medica, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 211198, China. Electronic address: chengtianle007@163.com.
  • 9 Department of Pharmacology, School of Pharmacy, China Pharmaceutical University, Nanjing 211198, China. Electronic address: zxqiu@cpu.edu.cn.
PMID: 41124864 DOI: 10.1016/j.biopha.2025.118665
Abstract

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.

Keywords

CYP450s; Corydalis saxicola Bunting total alkaloids; MASLD/MASH; PXR; Pharmacokinetic; Transporters.

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