The disposition and pharmacokinetics of alpidem, a new anxiolytic, in the rat.
The autoradiographic distribution, disposition, biliary excretion, and pharmacokinetics of alpidem in Sprague-Dawley rats were evaluated after iv or oral administration. Following i.v. administration, autoradiography showed that radioactivity was preferentially localized in lipid-rich tissues including central nervous system structures. After a 3-mg.kg-1 i.v. or oral dose of [14C]alpidem, more than 80% of the radioactivity were excreted in the feces over a 6-day period. Biliary excretion of radioactivity in vigile rats, about 74% of the dose over a 7-hr period after either iv or oral administration, showed that alpidem was well absorbed. The absolute bioavailability (13%) data indicated a high first-pass effect. Plasma pharmacokinetic parameters of alpidem were as follows: Vd = 5 liter.kg-1, Cl = 2.2 liter.h-1.kg-1, and terminal t 1/2 beta = 1.2-1.7 hr. Three metabolites with a pharmacological activity similar to that of alpidem were detected in plasma. They were eliminated from the central compartment with half-lives comparable to that of the parent drug. Alpidem crossed the blood-brain barrier following either i.v. or oral administration, resulting in cerebral levels 2.5 to 4 times greater than the plasma levels. Alpidem was eliminated from the central nervous system according a biphasic process with a t 1/2 alpha comparable in plasma and brain. Alpidem represented 94 and 63% of cerebral radioactivity 5 min after i.v. and oral administration, respectively. Two out of the three active plasma metabolites were detected in the brain.
Garrigou-Gadenne
D
D
Clinical Research Department, Synthelabo Recherche, Meudon-la-Foret.
Durand
A
A
Thenot
J P
JP
Morselli
P L
PL
D000284:Administration, Oral; D000818:Animals; D014151:Anti-Anxiety Agents / Q000493:pharmacokinetics*; D001345:Autoradiography; D001646:Bile / Q000378:metabolism; D001711:Biotransformation; D001921:Brain / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D006207:Half-Life; D007093:Imidazoles / Q000378:metabolism / Q000493:pharmacokinetics*; D007276:Injections, Intraventricular; D008297:Male; D011725:Pyridines / Q000378:metabolism / Q000493:pharmacokinetics*; D051381:Rats; D011919:Rats, Inbred Strains; D013050:Spectrometry, Fluorescence; D014018:Tissue Distribution
D014151:Anti-Anxiety Agents; D007093:Imidazoles; D011725:Pyridines; C052036:alpidem