Pharmacokinetics and tissue distribution analysis of ginsenoside Rh₃ in rats using a novel LC-MS/MS quantification...

Ginsenoside Rh3 (GRh₃), a rare ginsenoside, demonstrates diverse pharmacological activities in vitro; however, the lack of pharmacokinetic and tissue distribution data has limited its translation to in vivo applications. This study aimed to develop and validate a novel liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for quantifying GRh₃ in rat biological matrices and to characterize its pharmacokinetic profile and tissue distribution following oral administration.

A validated LC-MS/MS method was established for the quantification of GRh₃ in rat plasma and tissues. Male Sprague-Dawley rats received an oral dose of GRh₃ (100 mg/kg), and plasma samples were collected up to 72 h post-dose for pharmacokinetic analysis. Tissue samples (intestine, stomach, liver, brain, etc.) were collected at the time corresponding to the maximum plasma concentration for distribution analysis.

The LC-MS/MS method showed excellent precision, accuracy, and extraction recovery (≥ 85%), with minimal matrix effects. GRh₃ exhibited a prolonged elimination half-life (14.7 ± 1.7 h), a low clearance rate (13.0 ± 3.8 L/h/kg), and a high volume of distribution (280.4 ± 109.3 L/kg). Tissue distribution analysis revealed the highest GRh₃ concentrations in the intestine (15445.2 ng/g), followed by the stomach (2906.7 ng/g) and liver (1930.8 ng/g). Notably, GRh₃ was able to cross the blood-brain barrier, with significant accumulation observed in the hippocampus (520.0 ng/g).

The prolonged elimination and extensive tissue distribution of GRh₃, particularly its ability to penetrate the brain, indicate potential therapeutic benefits or neurotoxic risks involving the central nervous system. The mechanism underlying its blood-brain barrier permeability warrants further investigation, potentially involving transporter-mediated uptake or modulation of barrier integrity. These findings provide a foundation for optimizing GRh₃ dosing regimens and guiding future preclinical studies.