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Glutathione (GSH) is an antioxidant involved in many metabolic and cell cycle-associated cell functions. Increasing its plasma levels may have beneficial systemic effects and may be of therapeutic relevance. GSH intake via the oral route does not successfully enhance GSH in plasma, due to its metabolization in the gut. Hence, many attempts have been made to develop GSH derivatives able to easily cross the cell membranes and to enhance its oral bioavailability. S-Acetyl-glutathione (SAG) is a GSH precursor which is more stable in plasma, it is taken up directly by the cells and later converted to GSH. In this work we have performed a single dose, randomised, open-label, two-sequence, two-period, cross-over bioavailability study of SAG compared to GSH, as reference product, in healthy volunteers. 18 male and female subjects were randomly allocated to one of two sequences of products (GSH and SAG) in the two study periods according to randomisation and cross-over design. The primary endpoint of the study was to describe the pharmacokinetic profile of GSH in plasma after a single oral administration of SAG or GSH. Plasma levels of GSH, SAG, γGlu-Cys and Cys-Gly were determined by UPLC/MS at different time intervals within 24 hours of oral administration. The safety and tolerability profile of SAG and GSH was excellent. SAG was not quantifiable in any plasma sample, suggesting that deacetylation of SAG occurs rapidly. The levels of plasma γGlu-Cys and Cys-Gly did not differ significantly between the two treatments, whereas GSH concentrations showed an increase and a low peak both in plasma and in erythrocytes followed by a decline up to 24 h post-dose. Rate (Cmax) and extent (AUC0-t) of GSH absorption of plasma were higher after single dose of SAG powder than after the reference product. Tmax of GSH in plasma or in erythrocytes was not significantly different between treatments.

Oral Administration of S-acetyl-glutathione: Impact on the Levels of Glutathione in Plasma and in Erythrocytes of Healthy Volunteers