Pharmacokinetics of thyrotrophin-releasing hormone in patients in different thyroid states

Abstract

In view of recent reports suggesting that thyroid hormone control of TRH degradation occurs outside the central nervous system in animals, the effect of thyroid status on serum and tissue degradation of TRH in man was investigated. In six patients with hyperthyroidism and six patients with hypothyroidism, constant TRH infusions were carried out for determination of plasma clearance rate (PCR) and half-life of disappearance (t1/2) of TRH, with simultaneous determination of half-life of disappearance in serum in vitro (t1/2p). Using a kinetic model, this enabled the calculation of the half-life of disappearance in the extravascular tissue compartment (t1/2t). All patients were reinvestigated after they had become euthyroid. PCR, t1/2 and t1/2p were 22.1 +/- 3.4 ml/kg per min, 6.8 +/- 1.1 min and 17.3 +/- 6.7 min (means +/- S.D.) respectively in the euthyroid patients. The t1/2p was slightly but significantly prolonged during hyperthyroidism. The t1/2 was 5.6 min in the hyperthyroid patients compared with 9.4 min in the hypothyroid patients. The calculated t1/2t was 6.5 min in the euthyroid patients. In the patients with untreated hyperthyroidism, t1/2t was significantly reduced (22.7 +/- 10.7%; mean +/- S.D.), while it was considerably prolonged (41.1 +/- 24.6%) in patients with untreated hypothyroidism. The percentage reduction or prolongation of t1/2t was negatively correlated with the logarithm of the serum concentrations of thyroxine (r = 0.92) and tri-iodothyronine (r = 0.91) in the untreated patients. Thus, thyroid hormones induce alterations in the pharmacokinetics of TRH. This may partly be due to induction by thyroid hormones of membrane-bound pyroglutamyl aminopeptidase.