Abstract
Quantitative blood levels of thyrotropin-releasing hormone (TRH) were determined by a sensitive and specific radioimmunoassay after oral administration or intravenous injected of thyrotropin-releasing hormone tartrate monohydrate (TRH-T) in the rat, dog and human. A pharmacokinetic analysis after intravenous injection of the drug revealed biphasic elimination of the whole blood concentration following a two-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 micrograms/kg); a half-life in alpha-phase of 3.2 min and beta-phase of 18.1 min in the beagle-dog (dose: 146 micrograms/dog); a half-life in alpha-phase of 4.0 min and beta-phase of 20.4 min in the human (dose: 730 microgram/human). The absolute bioavailability 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.q. 20, 100, 500 mg/kg of TRH) compared with i.v. injection (dose: 500 microgram/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.q., 10, 20, and 100 mg/dog at TRH) compared with i.v. injection (dose: 146 micrograms/dog). Those of after meal in beagle-dogs were 6.0 and 2.3% at 2.92 and 29.2 mg/dog dosing levels (e.q. 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 X four, e.q. 8 mg of TRH) two hours after meal, was 2.0% on the average, and thyroid stimulating hormone levels were significantly increased by oral administration of TRH-T tablets.
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