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

Abstract

Plasma levels of .gamma.-butyrolactone-.gamma.-carbonyl-L-histidyl-L-prolinamide citrate (DN-1417), and TRH analog, were determined by a radioimmunoassay after oral or i.v. administration in rats and dogs. A pharmacokinetic analysis after i.v. injection revealed biphasic elimination of the plasma concentration following a 2 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. The absorption of DN-1417 in rats and dogs was proportional to the dose. 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 TRH.