LC-MS/MS-based metabolomics and PK/PD correlation analysis reveal the mechanism of hyperlipidemia treatment with Gastrodia elata fine powder.

Gastrodia elata Blume is used as both a food and a traditional medicine in East Asia. This study evaluated the lipid-lowering effects of G. elata fine powder (GFP) and the associated metabolic responses in Sprague-Dawley rats with high-fat diet (HFD)-induced hyperlipidemia. Thirty-five rats were assigned to seven groups: a normal-diet control, an untreated HFD model, three GFP groups (150, 300, or 500 mg kg-1 per administration, three times daily), and two positive-control groups receiving simvastatin or fenofibrate. Following a 6 week modeling period and a 2 week intervention, serum biochemical parameters, liver histology, and serum, urinary, and fecal metabolic profiles were assessed using biochemical assays, histological examination, and untargeted liquid chromatography-high-resolution mass spectrometry. A separate cohort of six hyperlipidemic rats received gastrodin (25 mg kg-1) for pharmacokinetic/pharmacodynamic (PK/PD) analysis. Compared with the untreated HFD group, medium- and high-dose GFP improved serum lipid profiles, reduced serum aminotransferase activities, and ameliorated hepatic histopathological changes. Metabolomic profiling revealed 14 urinary, 8 fecal, and 16 serum metabolites whose HFD-associated alterations shifted toward normal-control levels following high-dose GFP treatment. The associated pathways included phenylalanine metabolism, taurine and hypotaurine metabolism, and the tricarboxylic acid cycle. Gastrodin exhibited a biphasic plasma concentration-time profile, whereas responses of five endogenous metabolic markers lagged behind systemic drug exposure. These findings support the short-term lipid-lowering activity of GFP in HFD-fed rats and its association with changes in amino acid, bile-acid-related, and energy metabolism.