The effects of a single oral application of D-penicillamine (DPA, mean dosage 28 mg/kg body weight) on urinary copper (Cu) excretion and general renal function in six high-Cu supplemented sheep (Cu intake of 3.7 mg/day per kg body weight for 84 days) and four controls (Cu intake of 0.16 mg/day per kg body weight) were investigated to quantify induced cupruresis and the therapeutic effect of DPA as a decoppering agent. Changes in liver Cu concentration were examined before and after DPA treatment by liver biopsies. The influence of DPA treatment on general renal function was low. A 10-fold increase in renal Cu excretion was induced in both groups of sheep. Maximal Cu excretion was observed 4 h after DPA treatment, with mean values of 280 pmol/min per kg body weight in the high Cu group and 145 pmol/min per kg body weight in the controls. In the high Cu sheep, urinary Cu excretion within 24 h after DPA application was equivalent to only 0.42 +/- 0.26% of liver Cu content (mean concentration 347 +/- 124 mg/kg wet weight). Moreover, no effect of DPA on liver Cu concentration was evident. These findings demonstrate that a single application of DPA is not effective in inducing sufficient Cu loss from the bodies of Cu-loaded sheep.