Speciation analysis of the antirheumatic agent Auranofin and its thiol adducts by LC/ESI-MS and LC/ICP-MS

Abstract

Auranofin is a gold(I)-based pharmaceutical for the treatment of rheumatoid arthritis. Despite the fact that it has been used since the 1970s, its mode of action is still not fully understood. Auranofin undergoes ligand exchange reactions in vivo to generate reactive metabolites. In the present study, methods are developed for the analysis of Auranofin and its adducts with endogenously available thiols. Auranofin is characterized by liquid chromatography coupled to electrospray ionization mass spectrometry (LC/ESI-MS) and inductively coupled plasma mass spectrometry (LC/ICP-MS), respectively. Obtained data indicate that monomeric Auranofin is the main compound to undergo exchange reactions with added thiol ligands. Adduct formation of the gold species with glutathione and human serum albumin is simulated successfully in vitro and analyzed by LC/ESI-MS and LC/ICP-MS. While the thiol ligand of Auranofin is displaced, the remaining triethylphosphine gold structure may covalently bind to either glutathione or human serum albumin. Moreover, oxidation of the phosphine ligand by disulfides occurs in both reaction mixtures with the phosphine oxide as the resulting product. Reactions of Auranofin with the thiols are quantitatively traced over several days by ICP-MS. Based on the obtained data, a potential reaction pathway of Auranofin with the two thiols is proposed.