Pharmacokinetics of the anxiolytic beta-carboline derivative abecarnil in the mouse, rat, rabbit, dog, cynomolgus monkey and baboon. Studies on species differences.
The pharmacokinetics of abecarnil (isopropyl 6-(benzyloxy)-4-(methoxymethyl)-9H-pyrido [3,4-b] indole-3-carboxylate, ZK 112 119) were studied in the mouse, rat, rabbit, dog, cynomolgus monkey and baboon using 14C-labeled drug and HPLC with fluorescence detection for measurement of unchanged drug. Abecarnil was rapidly and completely absorbed after oral doses of 10 mg/kg. At higher doses, absorption was prolonged and incomplete in the cynomolgus monkey. The bioavailability of abecarnil was 20-30% in all the species investigated. The terminal half-life of the unchanged drug in plasma was relatively similar in all species (0.6-1.7 h). Abecarnil was able to pass the blood-brain barrier achieving concentrations in the brain similar to those in plasma. Tissue distribution of labeled compounds was rapid with highest concentrations in the liver, adrenals, kidneys and pancreas followed by the bone marrow, lungs, heart, fat, spleen, ovaries and thyroid gland. Excretion of radiolabeled compounds proceeded predominantly in the feces of the rat, the rabbit and the cynomolgus monkey.
Krause
W
W
Department of Pharmacokinetics, Schering Aktiengesellschaft, Berlin, Germany.
Mengel
H
H
D000818:Animals; D014151:Anti-Anxiety Agents / Q000493:pharmacokinetics*; D001345:Autoradiography; D001682:Biological Availability; D001812:Blood-Brain Barrier / Q000187:drug effects; D002243:Carbolines / Q000493:pharmacokinetics*; D004285:Dogs; D005260:Female; D006207:Half-Life; D007408:Intestinal Absorption; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D010215:Papio; D011817:Rabbits; D051381:Rats; D013045:Species Specificity; D014018:Tissue Distribution
D014151:Anti-Anxiety Agents; D002243:Carbolines; C062769:abecarnil