title: Nasal absorption of (S)-UH-301 and its transport into the cerebrospinal fluid of rats.
abstract: Targeting the brain via nasal administration of drugs has been studied frequently over the last few years. In this study, the serotonin-1a receptor antagonist (S)-5-fluoro-8-hydroxy-2-(dipropyl-amino) tetralin ((S)-UH-301) hydrochloride was used as a model substance. The systemic absorption and transport of (S)-UH-301 into male Sprague-Dawley rat cerebrospinal fluid (CSF) were investigated after nasal and intravenous administration. Blood and CSF samples were obtained at regular time intervals from the arteria carotis and by cisternal puncture, respectively, after administration to both nostrils (total 12 micromol/kg) or into the vena jugularis (6 micromol/kg). The concentrations of (S)-UH-301 in plasma and CSF were measured by HPLC with electrochemical detection. The maximum plasma concentration of intranasal (S)-UH-301 occurred in about 7 min and the absolute bioavailability seemed to be complete (F=1.2+/-0.4). Initially, no increased concentrations of (S)-UH-301 were seen in CSF after nasal compared to intravenous administration i.e. it appeared that no direct transport of (S)-UH-301 from the nasal cavity, along the olfactory neurons and into the CSF occurred. However, a prolonged duration of the concentration was seen after nasal administration of (S)-UH-301 and after about 20 min the CSF(na):CSF(iv) concentration ratio (corrected for different dosage) exceeded 1.
authors.affiliation: Department of Pharmacy, Division of Pharmaceutics, Biomedical Centre, Uppsala University, Box 580, SE-751 23, Uppsala, Sweden.
authors.forename: M
authors.initials: M
authors.lastname: Dahlin
authors.forename: E
authors.initials: E
authors.lastname: Björk
mesh_terms: D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics; D000042:Absorption; D000280:Administration, Inhalation; D000818:Animals; D019540:Area Under Curve; D001682:Biological Availability; D002851:Chromatography, High Pressure Liquid; D007275:Injections, Intravenous; D008297:Male; D009296:Nasal Cavity / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012702:Serotonin Antagonists / Q000008:administration & dosage / Q000097:blood / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics*; D014018:Tissue Distribution
chemical_list: D012702:Serotonin Antagonists; C064282:UH 301; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin