Effects of thyroid dysfunction on prednisolone and prednisone interconversion and disposition in the rat

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 μg of l-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 steriods in plasma were asseyed 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 hypothyriod 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 chearance rather than affecting the relative rates of steroid interconversion. Reversible metabolism is much less important in rats conpared to man.