title: Distribution of clozapine and desmethylclozapine between blood and brain in rats.
abstract: Desmethylclozapine is the major metabolite of clozapine in serum. Although the metabolite is pharmacologically active in vitro, the occurrence of desmethylclozapine in brain under steady-state conditions and its role for clinical actions of clozapine are unclear. In this study 20 male Sprague-Dawley rats received five oral doses of clozapine 20 mg/kg at 1.5-h intervals. At 0.5, 1, 2 and 5 h after the last administration, at a time four animals were killed for analysis of clozapine and desmethylclozapine concentrations in serum and brain. The treatment yielded steady-state serum concentrations of clozapine that are considered as therapeutically effective in man. Desmethylclozapine concentrations exceeded those of clozapine at 2-5 h after drug application. In brain, drug concentrations were 15.8-fold higher for clozapine than in serum, but only 2.7-fold higher for desmethylclozapine. The brain clozapine concentrations exceeded those of desmethylclozapine by about 3 times. These data indicate that desmethylclozapine is unlikely to play a role for CNS-mediated effects.
authors: Department of Psychiatry, University of Mainz, Germany.
authors: H
authors: H
authors: Weigmann
authors: S
authors: S
authors: Härtter
authors: V
authors: V
authors: Fischer
authors: N
authors: N
authors: Dahmen
authors: C
authors: C
authors: Hiemke
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000097:blood / Q000493:pharmacokinetics*; D001711:Biotransformation; D001921:Brain / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D003024:Clozapine / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D014150:Antipsychotic Agents; C058272:norclozapine; D003024:Clozapine