Clinical Pharmacokinetics of Oral and Injectable Gold Compounds

Abstract

The pharmacokinetics of oral gold (auranofin) in some respects resemble, and in other respects differ from, those of existing parenteral gold compounds such as gold sodium thiomalate (GST). This may in part relate to physicochemical differences as GST is a water-soluble polymeric compound in vitro whereas auranofin is lipid-soluble and characteristically monomeric. Furthermore, intramuscularly administered gold is greater than 95% bioavailable, whereas only 20 to 30% of an orally administered dose of auranofin is absorbed. Following a standard 50mg intramuscular injection of GST, serum gold concentrations rise sharply, peaking between 4 and 8 mg/L in approximately 2 hours and declining to an average of 3 mg/L by 7 days. With repeated injections of GST stable serum concentrations of gold (3 to 5 mg/L) are eventually achieved (usually within 5 to 8 weeks) although absolute concentrations may vary widely between patients. On the other hand, long term treatment with auranofin is associated with lower and more stable serum concentrations of gold (0.5 to 0.7 mg/L), on the standard dosing regimen of 6 mg daily. Both compounds are retained within the body for prolonged periods. However, the amount of gold retained with auranofin is significantly less compared with GST (less than 5% of a tracer dose of auranofin--about 20% of the absorbed dose--is retained by 100 days whereas the retention for a single labelled dose of GST over a similar interval is greater than 50%). Excretory patterns of GST and auranofin also differ. Most of an absorbed dose of GST (greater than 70%) is excreted by the kidneys whereas only 50% of an absorbed (15% of an administered) dose of auranofin is excreted in the urine. Both compounds are avidly bound by plasma proteins and auranofin shows a particularly strong association with circulating cellular elements. In human subjects, parenterally administered gold is widely distributed among bodily tissues, showing a predilection for tissues of the reticuloendothelial system as well as the kidney and adrenal cortex. Comparable studies in humans are not available for auranofin but animal studies have shown comparatively less affinity for the liver, kidney and spleen. Valuable insight has been gained in analysing the comparative pharmacokinetics of oral and injectable gold compounds. Unfortunately, attempts to correlate pharmacokinetic findings with clinical response or pharmacodynamic changes, as a whole, remain largely unsuccessful with these agents.

Atypical Protein Kinase Cι Expression and Aurothiomalate Sensitivity in Human Lung Cancer Cells

“…No signs of toxicity were observed in these mice. Serum gold levels exhibited a linear relationship over this dose range and drug levels achieved were consistent with the range of serum gold (3–5 µg/mL) typically observed in RA patients undergoing ATM therapy 11. Serum gold levels of 3–5 µg/mL correspond to ATM concentrations of 15.4–25.6 µM, well within the range of ATM concentrations exhibiting inhibitory effects on anchorage-independent growth of NSCLC cell lines in vitro.…”

Pro-apoptotic effect of aurothiomalate in prostate cancer cells

“…Serum levels of ATM in patients treated with this compound has been reported to be 3-8 μg/mL. 29,30 Interestingly, in a recent study by Regala et al 31 a potent antitumor effect of ATM on a small lung carcinoma cell line in vitro at IC 50 46 μmol/L was observed, which is consistent with our data, presented here. Thus, it appears that the presumed cytotoxic effects exerted by ATM on prostate cancer cells in vivo, could be achieved without (10 mM KCl, 1.5 mM MgCl 2 , 1 mM EDTA, 20 mM Hepes/Tris pH 7.4) supplemented with protease and phosphatase inhibitors.…”

Auranofin inactivates Trichomonas vaginalis thioredoxin reductase and is effective against trichomonads in vitro and in vivo

“…Oral dosing of auranofin in the treatment of rheumatoid arthritis produces steady-state blood plasma levels of 1–2 µM in humans [22], which are within the range of IC 50 values observed for T. vaginalis in vitro. Consistent with this, oral auranofin proved to be efficacious in eradicating vaginal trichomonad infection in mice.…”