The pharmacokinetics of thyrotropin-releasing hormone (TRH) were assessed following an i.v. injection in blood of ten hyperthyroid, ten hypothyroid, and six normal subjects. A single-compartment model was employed. After methanol extraction, TRH concentrations were analyzed using a specific radioimmunoassay technique combined with fast protein liquid chromatography (FPLC). As for the basal levels of TRH, no differences were observed in either study group. Peak concentrations were always present two min after the injection of TRH. In the euthyroid subjects, TRH blood levels had a half-life (t1/2) of 6.5 +/- 0.41 min, mean +/- SD, while t1/2 was 7.2 +/- 0.62 min in the hyperthyroid and t1/2 was 12 +/- 1.67 min (p less than 0.001) in the hypothyroid patients. The metabolic clearance rate (MCR) (82.2 +/- 15.3 liters/m2/day vs. 89.8 +/- 17.2) and the volume of distribution (Vd) (7.1 +/- 4.2 liters vs. 7.3 +/- 3.4) were approximately the same in the normal subjects and in the hyperthyroid group. MCR (66.2 +/- 15.3 liters/m2/day) and Vd (6.2 +/- 3.3 liters) were found to be lower in the hypothyroid patients. In FPLC, when TRH was added to plasma, it eluted in one peak. Blood samples taken 5 min after TRH i.v. injection had an elution profile of 9.94 ml. These data indicate that 1) TRH has a very short half-life, 2) hypothyroidism can prolong the t1/2 of exogenous TRH, and 3) when TRH should be used in clinical studies, the function of the thyroid gland has to be taken into consideration.