Enhanced bioavailability of a new class of dopamine D-1 antagonists following oral administration of their carbamic acid ester prodrugs to dogs

Abstract

Using specific high-pressure liquid chromatography (HPLC) methods, the pharmacokinetics of NNC 0112 and NNC 0756 were studied in mongrel dogs. Both compounds have a low oral bioavailability of 5.4 ± 3.6% (mean ± SD, n = 4) and 6.0 ± 0.5% ( n = 4), respectively, due to a large first-pass metabolism. Both compounds were rapidly cleared from the body with a total body clearance of 26.0–26.5 ml/min per kg, and terminal elimination half-lives of approx. 2 h. The high first-pass metabolism could be reduced using various mono- and disubstituted carbamate ester prodrugs previously characterized in vitro. The isopropyl monosubstituted carbamate ester increased the oral bioavailability of NNC 0112 3-fold, whereas the N, N-dimethyl-substituted carbamate ester improved the bioavailability to approx. 20%. The dimethyl- and diethyl-substituted carbamate esters of NNC 0756 increased the bioavailability to 30 and 14%, respectively, and a novel prodrug form based on the methyl ester of N-methylalanine improved the oral bioavailability of NNC 0756 approx. 3-fold.