Absorption of thyrotropin-releasing hormone after oral administration of TRH tartrate monohydrate in the rat, dog and human.

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Abstract
Quantitative blood levels of TRH were determined by a sensitive and specific radioimmunoassay after oral administration or i.v. injection TRH tartrate monohydrate (TRH-T) in the rat, dog and human. A pharmacokinetic analysis after i.v. injection of the drug revealed biphasic elimination of the whole blood concentration following a 2-compartment open model with a half-life in .alpha.-phase of 2.6 min and .beta.-phase of 4.6 min in the rat (dose: 500 .mu.g/kg); a half-life in .alpha.-phase of 3.2 min and .beta.-phase of 18.1 min in the beagle-dog (dose: 146 .mu.g/dog); a half-life in .alpha.-phase of 4.0 min and .beta.-phase of 20.4 min in the human (dose: 730 .mu.g/human). The absolute bioavailabilities of TRH after oral administration of TRH-T solution in 24 h fasting rats were 1.5, 0.4 and 0.2% at 29.2, 146 and 730 mg/kg dosing levels, respectively (e.g. 20, 100, 500 mg/kg of TRH) compared with i.v. injection (dose: 500 .mu.g/kg). In beagle-dogs, they were 12.6, 9.8, 5.6 and 3.5% at 2.92, 14.6, 29.2 and 146 mg/dog dosing levels, respectively (e.g. 2, 10, 20 and 100 mg/dog of TRH) compared with i.v. injection (dose: 146 .mu.g/dog). Bioavailabilities after a meal in beagle-dogs were 6.0 and 2.3% at 2.92 and 29.2 mg/dog dosing levels (e.g. 2 and 20 mg/dog of TRH). Thus, TRH absorption showed apparent saturation and was decreased by food ingestion. The absolute bioavailability in the humans, who were administered 11.7 mg TRH-T (2.92 mg/tablet .times. 4, e.g. 8 mg of TRH) 2 h after a meal, was 2.0% on the average TSH levels were significantly increased by oral administration of TRH-T tablets.