An integrative pharmacokinetic and pharmacodynamic study of the 5-HT1A receptor antagonist (S)-UH-301 in the rat.
(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 mumol/kg). However, at doses above 32 mumol/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 mumol/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 mumol/kg s.c., corresponding to concentrations below approximately 10 nmol/g in brain and approximately 1 nmol/ml in plasma.
Yan
Hongmei
H
Department of Neuroscience, Psychiatry, Ulleråker, Uppsala University, 750 17 Uppsala, Sweden. hongmei.yan@ullpsyk.uu.se
Yu
Hong
H
Lewander
Tommy
T
D006916:5-Hydroxytryptophan / Q000378:metabolism; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D000818:Animals; D019540:Area Under Curve; D001831:Body Temperature / Q000187:drug effects / Q000502:physiology; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D007980:Levodopa / Q000378:metabolism; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D011985:Receptors, Serotonin / Q000378:metabolism; D044263:Receptors, Serotonin, 5-HT1; D012702:Serotonin Antagonists / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology
D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D012702:Serotonin Antagonists; C064282:UH 301; D007980:Levodopa; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D006916:5-Hydroxytryptophan