title: Regional brain distribution of risperidone and its active metabolite 9-hydroxy-risperidone in the rat.
abstract: Risperidone is a new benzisoxazole antipsychotic. 9-Hydroxy-risperidone is the major plasma metabolite of risperidone. The pharmacological properties of 9-hydroxy-risperidone were studied and appeared to be comparable to those of risperidone itself, both in respect of the profile of interactions with various neurotransmitters and its potency, activity, and onset and duration of action. The absorption, plasma levels and regional brain distribution of risperidone, metabolically formed 9-hydroxy-risperidone and total radioactivity were studied in the male Wistar rat after single subcutaneous administration of radiolabelled risperidone at 0.02 mg/kg. Concentrations were determined by HPLC separation, and off-line determination of the radioactivity with liquid scintillation counting. Risperidone was well absorbed. Maximum plasma concentrations were reached at 0.5-1 h after subcutaneous administration. Plasma concentrations of 9-hydroxy-risperidone were higher than those of risperidone from 2h after dosing. In plasma, the apparent elimination half-life of risperidone was 1.0 h, and mean residence times were 1.5 h for risperidone and 2.5 h for its 9-hydroxy metabolite. Plasma levels of the radioactivity increased dose proportionally between 0.02 and 1.3 mg/kg. Risperidone was rapidly distributed to brain tissues. The elimination of the radioactivity from the frontal cortex and striatum--brain regions with high concentrations of 5-HT2 or dopamine-D2 receptors--became more gradual with decreasing dose levels. After a subcutaneous dose of 0.02 mg/kg, the ED50 for central 5-HT2 antagonism in male rats, half-lives in frontal cortex and striatum were 3-4 h for risperidone, whereas mean residence times were 4-6 h for risperidone and about 12 h for 9-hydroxy-risperidone. These half-lives and mean residence times were 3-5 times longer than in plasma and in cerebellum, a region with very low concentrations of 5-HT2 and D2 receptors. Frontal cortex and striatum to plasma concentration ratios increased during the experiment. The distribution of 9-hydroxy-risperidone to the different brain regions, including frontal cortex and striatum, was more limited than that of risperidone itself. This indicated that 9-hydroxy-risperidone contributes to the in vivo activity of risperidone, but to a smaller extent than would be predicted from plasma levels. AUCs of both active compounds in frontal cortex and striatum were 10-18 times higher than those in cerebellum. No retention of metabolites other than 9-hydroxy-risperidone was observed in any of the brain regions investigated.
authors.affiliation: Department of Drug Metabolism and Pharmacokinetics, Janssen Research Foundation, Beerse, Belgium.
authors.forename: L E
authors.initials: LE
authors.lastname: van Beijsterveldt
authors.forename: R J
authors.initials: RJ
authors.lastname: Geerts
authors.forename: J E
authors.initials: JE
authors.lastname: Leysen
authors.forename: A A
authors.initials: AA
authors.lastname: Megens
authors.forename: H M
authors.initials: HM
authors.lastname: Van den Eynde
authors.forename: W E
authors.initials: WE
authors.lastname: Meuldermans
authors.forename: J J
authors.initials: JJ
authors.lastname: Heykants
mesh_terms: D000818:Animals; D000932:Antiemetics / Q000494:pharmacology; D014150:Antipsychotic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D001058:Apomorphine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D001921:Brain / Q000378:metabolism*; D004285:Dogs; D006207:Half-Life; D007279:Injections, Subcutaneous; D007555:Isoxazoles / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D008297:Male; D014179:Neurotransmitter Uptake Inhibitors / Q000494:pharmacology; D009638:Norepinephrine / Q000494:pharmacology; D009929:Organ Size / Q000187:drug effects; D000068882:Paliperidone Palmitate; D010880:Piperidines / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D011743:Pyrimidines / Q000493:pharmacokinetics*; D051381:Rats; D017208:Rats, Wistar; D017981:Receptors, Neurotransmitter / Q000187:drug effects; D018967:Risperidone; D013056:Spectrophotometry, Ultraviolet; D014363:Tryptamines / Q000494:pharmacology
chemical_list: D000932:Antiemetics; D014150:Antipsychotic Agents; D007555:Isoxazoles; D014179:Neurotransmitter Uptake Inhibitors; D010880:Piperidines; D011743:Pyrimidines; D017981:Receptors, Neurotransmitter; D014363:Tryptamines; D018967:Risperidone; D001058:Apomorphine; D000068882:Paliperidone Palmitate; D009638:Norepinephrine