Pharmacokinetic changes and mechanisms of salidroside in hypobaric hypoxic environment: A LC-MS and proteomics study

Salidroside (Sal), the main active component of Rhodiola, is commonly used to alleviate altitude sickness and enhance hypoxia tolerance. However, its rapid metabolism and low oral bioavailability have limited its pharmaceutical development. Additionally, the impact of hypobaric hypoxic environments on its in vivo metabolism and the underlying mechanisms remains unclear.

The purpose of this investigation was to elucidate the pharmacokinetic changes of salidroside in a hypobaric hypoxic environment and explore its potential mechanisms.

An efficient and rapid liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay was developed to determine Sal and investigate pharmacokinetic changes. The potential mechanisms of changes were explored through the application of proteomics and molecular docking, combined with various cellular and tissue models.

Hypobaric hypoxia significantly increased the in vivo exposure of Sal and reduced its clearance, with the bioavailability of Sal increasing by approximately 108 % under hypoxia versus normoxia. The mechanisms involved in upregulating sodium-glucose cotransporter 1 (SGLT1) to promote intestinal absorption of Sal. Phosphoglycerate mutase 1 (PGAM1) was found to diminish the activity of hepatic metabolic enzymes by modulating glycolysis, which decreased the clearance of Sal. Sal concentrations were relatively high in the heart, lung, and spleen. It was mainly excreted via the kidneys in the form of tyrosol (Tyr), and hypoxia slowed this excretion process. Sal demonstrated limited permeability across the blood-brain barrier (BBB), while Tyr had significantly higher BBB permeability. Hypoxia also enhanced P-glycoprotein (P-gp)-mediated Tyr efflux.

This study conducted a comprehensive analysis of Sal pharmacokinetic changes in a hypobaric hypoxic environment, providing critical insights for optimizing the clinical application of Sal in plateau diseases.