Extensive gastrointestinal metabolic conversion limits the oral bioavailability of the dopamine D2 agonis N-0923 freely moving rats

The absorption of the dopamine D2 agonist S(-)-2-(N-propyl-N-2-thienylethylamino)-5-hydroxy-tetralin hydrochloride (1; N-0923) was studied in fasted and non-fasted male Albino Wistar rats after intragastric administration of 10.0 mumol . kg-1. Blood samples up to 120 min were obtained from the portal vein and the levels of 1 were monitored with a sensitive HPLC method.

The maximal fraction of the drug reaching the liver invariable was less than 1% of the dose. Maximal plasma levels of 30 pmol . ml-1 were found within 12 min after dosing in fasted animals. Plasma concentrations of 1 were measurable up to 60 min, after which they were below the quantitation limit of the assay (10 pmol . ml-1). This did not allow detailed kinetic analysis.

Analysis of -the portal blood samples obtained after an oral dosing of 10.0 mumol . kg-1 1 spiked with 0.37 MBq tritium labelled drug showed that the amount of unchanged drug which reaches the liver invariably was comparable with the concentrations found in the study without radioactivity.

In vitro incubation of 1 with gastric juice and gut contents showed no degradation. Therefore, it can be concluded that 1 undergoes an extensive metabolism in the gastrointestinal mucosa.