We found this particular case during the course of a clinical trial designed to assess the pharmacokinetics of oral prednisone in normal and diseased children. The plasma concentrations of prednisone, its main metabolite prednisolone, and endogenous cortisol were measured by HPLC at selected times during 8-h periods starting at 7:30 a.m. One 9.9-year-old administered prednisone 0.5mg/kg p.o. was found to be hypothyroid (TSH: 351microIU/mL; fT4: <2pg/mL; fT3: <1pg/mL); four age-matched normal boys (aged 6.6+/-4.9 years) served as a control group. In comparison with the controls, the hypothyroid boy showed a marked increase in the total AUC of prednisone (3360microg h/L versus 215+/-83microg h/L) and prednisolone (4040microg h/L versus 724+/-77microg h/L), and an altered pattern of endogenous cortisol, which is known to be impaired in hypothyroid subjects. After 6 months of thyroxine replacement therapy (75microg/day), the AUCs of prednisone and prednisolone returned to normal values (prednisone: 248microg h/L; prednisolone: 528microg h/L), as did the pattern of circadian cortisol secretion. In conclusion, our data indicate that the pharmacokinetics of prednisone and prednisolone can be profoundly altered by hypothyroidism, and subsequently restored by thyroxine replacement therapy.