Rapid communicationPharmacokinetics of prednisone and prednisolone in a case of hypothyroidism: Effect of replacement therapy
Introduction
Thyroid disease changes the pharmacokinetics of many drugs by physiologically altering intestinal transit times, hepatic microsomal enzyme activity, cardiac output, renal plasma flow, hepatic blood flow and plasma protein binding [1]. Little information is available concerning hypothyroidism, in which the absorption of paracetamol and propranolol is decreased, that of riboflavin is increased, and the distribution volume of digoxin is reduced [1]. The high steady-state propranolol concentrations in hypothyroid patients in comparison with the same patients after thay have been made euthyroid suggests decreased hepatic metabolism [1]. There are changes in hormonal clearance, with decreased cortisol and thyroid hormone metabolism [1], and the renal clearance of digoxin and practolol seems to be reduced [1].
The availability of prednisone and prednisolone has not yet been examined in hypothyroid humans, but it has been reported that their pharmacokinetic parameters are altered in hypothyroid rats [2]. It is also well known that patients receiving ‘standard’ daily doses may show considerable differences in terms of therapeutic response and the incidence of side effects [3]. Although this variability can be partially explained by differences in disease severity, pharmacokinetic factors may also be important.
We here report the case of a boy who took prednisone during the course of a clinical trial designed to assess the pharmacokinetics of oral prednisone in normal and diseased children, and who was diagnosed as being hypothyroid 2 days after drug intake. We also determined whether the alterations in the pharmacokinetics of prednisone and prednisolone in this hypothyroid child could be restored by the replacement therapy with thyroxine.
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Patients and protocol
An otherwise healthy boy aged 9.9 years was included in a clinical trial designed to assess the pharmacokinetics of oral prednisone in normal and diseased children. Shortly after receiving a single oral dose of prednisone 0.5 mg/kg, he was found to be hypothyroid (TSH: 351 μIU/mL; fT4: <2 pg/mL; fT3: <1 pg/mL); he underwent the same test after 6 months of thyroxine replacement therapy (75 μg/day; Eutirox™, Bracco, Milan, Italy).
Four aged-matched normal boys (aged 6.6 ± 4.9 years) enrolled in the same
Results
In comparison with the controls, the hypothyroid boy showed a marked increase in the total AUCs of prednisone and prednisolone, with Tmax at 6 h (Fig. 1; Table 1). As shown in Fig. 1, the typical circadian secretion of cortisol with zenith in the early morning was absent.
After 6 months of thyroxine replacement therapy (TSH: 7.04 μIU/mL; fT4: 13.06 pg/mL; fT3: 3.05 pg/mL), the AUCs of prednisone and prednisolone returned to normal values (Fig. 1; Table 1), as did Tmax (3 h) (Table 1) and the pattern
Discussion
This report provides the first clinical evidence of the altered pharmacokinetics of prednisone and prednisolose in hypothyroidism. In comparison with the controls, our hypothyroid boy showed a marked increase in the total AUCs of prednisone and prednisolone, and the lack of endogenous cortisol zenith in the early morning, a clear sign of an altered circadian pattern, which is known to be impaired in hypothyroid subjects [1], [6]. Although many diseases can affect drug pharmacokinetics, our
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Present address: Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena, FRCCS, Department of Endocrinology, Milan, Italy.