Effects of tetrathiomolybdate on copper metabolism in healthy volunteers and in patients with Wilson disease

Background & Aims: In Wilson disease (WD), copper accumulates in the liver and brain causing disease. Bis-choline tetrathiomolybdate (TTM) is a potent copper chelator that may be associated with a lower risk of inducing paradoxical neurological worsening than conventional therapy for neurologic WD. To better understand the mode of action of TTM, we investigated its effects on copper absorption and biliary excretion. Methods: In a double-blind randomized setting, hepatic 64 Cu activity was examined after orally administered 64 Cu by PET/CT in 16 healthy volunteers before and after seven days of TTM treatment (15 mg/d) or placebo. Oral 64 Cu was administered one hour after the final TTM dose. Changes in hepatic 64 Cu activity reflected changes in intestinal 64 Cu uptake. Additionally, in four patients with WD, the distribution of 64 Cu in venous blood, liver, gallbladder, kidney, and brain was followed after i.v. 64 Cu dosing for up to 68 hours before and after seven days of TTM (15 mg/day), using PET/MRI. Increased gallbladder 64 Cu activity was taken as evidence of increased biliary 64 Cu excretion. Results: In healthy volunteers, TTM reduced intestinal 64 Cu uptake by 82% 15 hours after the oral 64 Cu dose. In patients with WD, gallbladder 64 Cu activity was negligible before and after TTM, while TTM effectively retained 64 Cu in the blood, significantly reduced hepatic 64 Cu activity at all time -points and significantly reduced cerebral 64 Cu activity two hours after the intravenous 64 Cu dose. Conclusions: While we did not show an increase in biliary excretion of 64 Cu following TTM administration, we demonstrated that TTM effectively inhibited most intestinal 64 Cu uptake and retained 64 Cu in the blood stream, limiting the exposure of organs like the liver and brain to 64 Cu.