Model-based compartmental analysis was used to describe data on the whole body kinetics of copper metabolism in rats. Data were collected on recovery of radio-copper in plasma, liver, skin, skeletal muscle, bile, and feces for 3 days after the injection of 10 micrograms iv of copper labeled with 64Cu. Data on copper masses and on 64Cu kinetics were analyzed by the stimulation, analysis, and modeling computer programs. Observed data were fit to a 16-component "working hypothesis" model; fractional transfer coefficients were estimated, and steady-state compartment masses and copper transfer rates were calculated. The model postulates a rapid turnover of plasma nonceruloplasmin (NCp) copper (8.5 h-1), which exchanged a large amount of copper with extrahepatic tissues (16 micrograms/h) as well as liver (13 micrograms/h). In comparison, ceruloplasmin (Cp) transferred relatively little copper to tissues (less than 1 microgram/h). NCp copper is postulated to be the precursor for biliary copper. Regarding the intracellular metabolism of copper in hepatic and extrahepatic tissues, the data were compatible with a faster turning-over compartment that exchanged copper with NCp and a slower turning-over compartment with input from Cp. In the liver, the slower turning-over compartment was the copper present in peak II (mol mass 30,000-40,000 Da); this received much of its input from the faster turning-over compartment (peak III), which was hypothesized to represent, in large part, copper in metallothionein.