An integrative pharmacokinetic and pharmacodynamic study of the 5-HT1A receptor antagonist (S)-UH-301 in the rat

Abstract ( S )-UH-301 ((−)-( S )-5-fluoro-8-hydroxy-2-(di- n -propylamino)tetralin hydrochloride) is a well known 5-HT 1A receptor antagonist. The present study describes the pharmacokinetic properties of ( S )-UH-301 after subcutaneous administration in rats, using a newly developed HPLC–UV bioanalytical method. The relationships between ( S )-UH-301 concentrations and some pharmacodynamic effects were also studied. The AUC of ( S )-UH-301 in brain, but not in plasma, increased in proportion to dose (1–100 μmol/kg). However, at doses above 32 μmol/kg, peak concentrations of the drug did not increase in proportion to dose, and there was a doubling of its apparent half-life. There was a good correspondence between the time courses for the antagonism of 8-OH-DPAT-induced motor behaviours and hypothermia and the tissue concentrations of ( S )-UH-301. Doses of ( S )-UH-301 above 10 μmol/kg decreased 5-HT and dopamine synthesis. Therefore, a selective 5-HT 1A antagonistic dose range of ( S )-UH-301 should be 0.1–10 μmol/kg s.c., corresponding to concentrations below ≈10 nmol/g in brain and ≈1 nmol/ml in plasma.