The effects of thyroid dysfunction on the reversible metabolism and disposition of prednisolone and prednisone were examined in male Wistar rats. Hyperthyroid rats were produced by daily ip injections of 20 micrograms of I-triiodothyronine/100 g body weight for 6 days. Hypothyroid rats were obtained by providing 0.05% 6-propyl-2-thiouracil in drinking water ad libitum for 21 days. Rats were given 10 mg/kg of prednisolone or prednisone iv, blood samples were collected, and the steroids in plasma were assayed by HPLC. A recently developed pharmacokinetic model encompassing interconversion kinetics was applied. Unexpectedly, the hyperthyroid state increased the AUC (by 163%) of prednisolone (unlike in man) via reduced (66%) prednisolone elimination clearance (CL10), but also caused enhanced (101%) prednisone elimination clearance (CL20). The hypothyroid state increased the AUC (by 117%) of prednisolone via a 56% reduction in CL10 and a reduction in CL20. Prednisone formation of prednisolone (CL21) was about 13-fold greater than the reverse process (CL12), and both interconversion clearances were increased 20-40% by thyroid dysfunction. Experimental thyroid disorders thus alter prednisolone/prednisone pharmacokinetics in rats primarily by selective and sometimes unusual changes in elimination clearance rather than affecting the relative rates of steroid interconversion. Reversible metabolism is much less important in rats compared to man.