N6,2'-O-dibutyryladenosine 3',5'-cyclic monophosphate (Bt2cAMP) administration to rats is shown to reduce serum zinc levels and increase liver zinc and metallothionein significantly. Such redistribution is similar to that seen in the acute phase response to stress. To determine the sites of regulation of zinc metabolism involved in zinc redistribution, we compared the kinetics of intravenously administered 65Zn between control and Bt2cAMP-treated rats. 65Zn disappeared more rapidly from the plasma of Bt2cAMP rats, whereas 65Zn content of liver and liver metallothionein was increased. 65Zn in spleen and bone marrow also increased. No change was seen in muscle or kidney, and 65Zn content decreased in skin, bone, small intestine, and feces. These kinetic data were integrated into two compartmental models describing zinc metabolism in control and Bt2cAMP-treated states. Models were constructed using the SAAM and CONSAM modeling programs. Comparison of models suggest several sites of regulation due to Bt2cAMP. Zinc uptake into liver metallothionein from both plasma and other zinc pools within the liver was increased, whereas the release of metallothionein-bound zinc to plasma decreased. These changes increased liver zinc at the expense of plasma zinc, tissue zinc (principally skin, bone, and small intestine), and fecal zinc excretion. Bone marrow, spleen, and muscle were protected against zinc loss due primarily to decreased rates of tissue zinc loss. It was also postulated that Bt2cAMP increased the transfer of liver zinc to secreted alpha 2-macroglobulin. These results demonstrate that Bt2cAMP-induced zinc redistribution is tissue specific and related in part to metallothionein synthesis.