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Plasma levels of gamma-butyrolactone-gamma-carbonyl-L-histidyl-L-prolinamide citrate (DN-1417), an analog of thyrotropin-releasing hormone, were determined by a radioimmunoassay after oral or intravenous administration in rats and dogs. A pharmacokinetic analysis after intravenous injection revealed biphasic elimination of the plasma concentration following a two compartment open model with half lives in alpha-phase of 2.0 min and beta-phase of 19.2 min in rats, and half lives in alpha-phase of 4.0 min and beta-phase of 33.0 min in dogs. Absolute bioavailabilities when administered orally the solution of DN-1417 after 24 h fasting in rats and dogs were 1 and 10%, respectively. The bioavailability was observed to be unchanged at the dose up to 500 mg/kg in rats and at the dose up to 100 mg/dog in dogs. Thus, the absorption of DN-1417 in rats and dogs was proportional to the dose. On the other hand, the absolute bioavailabilities after meal in dogs were 7.9% at the dose of 20 mg/dog and 7.2% at the dose of 2 mg/dog, whereas in the 24 h fasting condition they were 15.7 and 12.0%, respectively, showing the decrease in absorption with food ingestion. These phenomena are somewhat different from the absorption of thyrotropin-releasing hormone.

journal of pharmacobio-dynamics

Absorption of .GAMMA.-butyrolactone-.GAMMA.-carbonyl-L-histidyl-L-prolinamide citrate (DN-1417), an analog of thyrotropin-releasing hormone, in rats and dogs.