Pharmacokinetics of the dopamine D2 agonist S(-)-2-(N-propyl-N-2-thienylethylamino)-5-hydroxytetralin in freely moving rats.

Abstract The pharmacokinetics of the dopamine D2 agonist S(–)-2- (N-propyl-N-2-thienylethylamino)-5-hydroxytetralin (1, N-0923) after intravenous, intraperitoneal, and oral administration was studied in freely moving male and female albino Wistar rats. In all cases, the dose was 10 μ mol ∙ kg -1 . Levels of 1 in plasma were monitored up to 6 h after dosing by high-performance liquid chromatography. A biphasic disap-pearance pattern with a rapid distribution phase was observed in the curve of concentration in plasma versus time. Pharmacokinetic analysis based on a two-compartment model with elimination from the central compartment yielded the following parameters for male rats (mean ± standard deviation, n = 3): elimination half-life was 108 ± 7 min, apparent volume of distribution of the central compartment was 397 ± 44 mL ∙ kg -1 , the plasma clearance was 32 ± 4mL ∙ min -1 ∙ kg -1 , and the apparent volume of distribution at steady state was 2.29 ± 0.25 L ∙ kg -1 . No significant difference (analysis of variance p value > 0.25) was found in the pharmacokinetic data between male and female rats. An extremely fast absorption was found after intraperitoneal administration. Maximal concentrations in plasma were often observed at the first time point 5 min after dosing. The bioavailability (mean ± standard deviation, n = 3) was 7.9 ± 2.7% for male rats and 6.5 ±2.1% for female rats. An increase of the elimination half-life of at least 40% for male rats and 300% for female rats was observed, indicating dose-dependent kinetics after intraperitoneal administration. After oral dosing, levels of 1 in plasma were extremely low and often below the quantitation limit of the assay (10 pmol ∙ mL -1 ). This did not allow detailed kinetic analysis. Even in the more favorable cases, the bioavailability did not exceed 0.5%. Although the 5-O-glucuronide and 5-sulfate are the major metabolites of 1, they could not be detected in plasma, indicating efficient excretion into bile and urine.