Gold drugs have successfully treated rheumatoid arthritis for over fifty years. The recently licensed drug auranofin provides a new oral route for administering chyrsotherapy. Yet, the mechanism of action of chrysotherapy remains uncertain. Gold drugs are unique in that they undergo rapid metabolism in the form of ligand exchange reactions with blood cells, proteins and thiols. The identity of the protein-gold metabolites that form and circulate after absorption of the parenteral and oral gold complexes have not yet been identified. As a result, researchers studying the effects of gold on the immune system and other target systems rely on the drugs themselves, which may in fact be irrelevant. We propose to study the blood chemistry of auranofin, the orally effective form of gold. We seek to understand the mechanisms of its ligand exchange reactions, especially the oxidation of the triethylphosphine ligand which renders it orally effective, and to identify the ligands bound to gold after it enters the red blood cell and when effluxes back into the serum. These circulating metabolites are likely to be the active agents which donate gold to the target systems. The principle methods employed will be in vitro studies of the reactions of auranofin and its initial metabolites (for example, the albumin-gold-phosphine complex), with blood components of successively greater complexity. Mechanistic studies will include structure-function relationships for modifications of the phosphine and thiolate ligands of auranofin in an albumin model for phosphine oxidation. Glutathione in red cells will be radiolabelled in situ, incorporating 14C- glycine via the glutathione cycle. H2 18O and H2 17O will be used to identify the sources of oxygen in Et3PO, an auranofin metabolite. The analytical tools include High Pressure Liquid chromatography, Gas Chromatography--Mass Spectroscopy, 31P and 17O Nuclear Magnetic Resonance, and Scintillation Counting (including double label studies utilizing 3H- Et3P195 AuSATg), Atomic Absorption Spectroscopy and UV-Visible Spectroscopy. In addition to providing insights into the gold species that should be used for in vitro mechanism of action studies, the information obtained facilitate the rational synthesis of second-generation oral drug with ligands that can potentiate the pharmacological profile of gold.
| Shaw 3rd, C F; Isab, A A; Coffer, M T et al. (1990) Gold(I) efflux from auranofin-treated red blood cells. Evidence for a glutathione-gold-albumin metabolite. Biochem Pharmacol 40:1227-34 |
| Isab, A A; Shaw 3rd, C F (1990) Synthesis of thionato(triethylphosphine) gold(I) complexes:analogues of ""auranofin,"" an antiarthritic drug. J Inorg Biochem 38:95-100 |
