A Targeted Metabolomic Assessment of Oral Glutathione Bioavailability and Safety in Humans: A Randomized Crossover Clinical Trial

Glutathione (GSH), often referred to as the “master antioxidant,” plays a vital role in protecting cells against oxidative stress. This human pilot study aimed to evaluate the oral absorption and safety profile of a novel formulation of micellar glutathione (LipoMicel^®, LMG) compared with two commonly used dietary supplement forms: standard glutathione (STD) and liposomal glutathione (Setria^® Glutathione, LSG). In the first phase, a randomized, double-blind, crossover study was conducted in healthy adults (n = 14) to assess whole-blood GSH following single oral doses using baseline-adjusted pharmacokinetic parameters (incremental AUC_0–24 [iAUC_0–24], C_max, T_max) and a targeted panel of glutathione-related metabolites. In the second phase, a 30-day, single-arm follow-up assessed the safety and tolerability of the most bioavailable formulation (LMG) in the same participants. Compared with STD (500 mg), LMG (300 mg) produced significantly higher baseline-adjusted systemic GSH exposure and peak response (iAUC_0–24: 1287.5 ± 179.0 vs. 517.8 ± 180.0 µg·mL·h; p = 0.0064; ΔC_max: 103.9 ± 11.8 vs. 42.8 ± 11.5 µg/mL; p = 0.0003), corresponding to ~2.49-fold higher incremental exposure and ~2.43-fold higher peak response at the administered doses. When dose-normalized to a 300 mg equivalent, the incremental exposure (iAUC) and C_max were up to 4-fold higher for LMG than STD. In the targeted metabolite panel, most analytes showed no formulation-dependent differences; however, dose-normalized methionine exposure was significantly higher with LMG than STD (iAUC: 149.9 ± 30.8 vs. 32.7 ± 28.3 µg·mL·h; p = 0.0151; ~4.58-fold). No significant differences were observed in oxidized glutathione (GSSG) exposure, while the GSH/GSSG ratio was higher following LMG versus STD (p = 0.001). No significant changes in clinical safety markers (e.g., ALT, AST, ALP, creatinine) were observed following 30 days of daily LMG administration at 600 mg/d. The novel micellar glutathione formulation demonstrated enhanced oral bioavailability compared with a standard glutathione preparation and was well tolerated over 30 days in healthy adults. These findings present LipoMicel^® as a promising approach for oral glutathione delivery and warrant further investigation into its long-term physiological and clinical effects. This clinical trial was registered at ClinicalTrials.gov under trial ID NCT06345950 on 3 April 2024.