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 2 h 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.
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Awouters FHL, Niemegeers CJE, Megens AAHP, Janssen PAJ (1990) Functional interaction between serotonin-S2 and dopamine-D2 neurotransmission as revealed by selective antagonism of hyperreactivity to tryptamine and apomorphine. J Pharmacol Exp Ther 254:945–951
Bouthenet M-L, Martres M-P, Salès N, Schwartz J-C (1987) A detailed mapping of dopamine D-2 receptors in rat central nervous system by autoradiography with [125I]iodosulpride. Neuroscience 20:117–155
Chan KK (1982) A simple integrated method for drug and derived metabolite kinetics: an application of the statistical moment theory. Drug Metab Dispos 10:474–479
Claus A, Bollen J, De Cuyper H, Eneman M, Malfroid M, Peuskens J, Heylen S (1992) Risperidone versus haloperidol in the treatment of chronic schizophrenic inpatients: a multicentre double-blind comparative study. Acta Psychiatr Scand 85:295–305
Cohen BM, Babb S, Campbell A, Baldessarini RJ (1988) Persistence of haloperidol in the brain. Arch Gen Psychiatry 45:878–880
Colburn WA, Jack ML (1987) Relationships between CSF drug concentrations, receptor binding characteristics, and pharmacokinetic and pharmacodynamic properties of selected 1,4-substituted benzodiazepines. Clin Pharmacokinet 13:179–190
Gelders YG, Heylen SLA, Vanden Bussche G, Reyntjens AJM, Janssen PAJ (1990) Pilot clinical investigation of risperidone in the treatment of psychotic patients. Pharmacopsychiatry 23:206–211
Gibaldi M, Perrier D (1982) Pharmacokinetics, 2nd edn. Dekker, New York Basel
Huang M-L, Van Peer A, Woestenborghs W, De Coster R, Heykants J, Janssen A, Zylicz Z, Visscher H, Jonkman J (1993) Pharmacokinetics of the novel antispsychotic agent risperidone and the prolactin response in healthy subjects. Clin Pharmacol Ther 54:252–268
Janssen PAJ, Niemegeers CJE, Awouters FHL, Schellekens KHL, Megens AAHP, Meert TF (1988) Pharmacology of risperidone (R 64 766), a new antipsychotic with serotonin-S2 and dopamine-D2 antagonistic properties. J Pharmacol Exp Ther 244:685–693
Kirch DG, Bigelow LB, Korpi ER, Wagner RL, Zalcman S, Wyatt RJ (1988) Serum haloperidol concentrations and clinical response in schizophrenia. Schizophrenia 14:283–289
Leysen JE, Geerts R, Gommeren W, Verwimp M, Van Gompel P (1982) Regional distribution of serotonin-2 receptor binding sites in the rat and effects of neuronal lesions. Arch Int Pharmacodyn Ther 256:301–305
Leysen JE, Gommeren W, Eens A, de Chaffoy de Courcelles D, Stoof JC, Janssen PAJ (1988) Biochemical profile of risperidone, a new antipsychotic. J Pharmacol Exp Ther 247:661–670
Leysen JE, Janssen PMF, Gommeren W, Wynants J, Pauwels PJ, Janssen PAJ (1992) In vitro and in vivo receptor binding and effects on monoamine turnover in rat brain regions of the novel antipsychotics risperidone and ocaperidone. Mol Pharmacol 41:494–508
Lewi PJ, Heykants, JJP, Allewijn FTN, Dony JGH, Janssen PAJ (1970) Distribution and metabolism of neuroleptic drugs, part 1: pharmacokinetics of haloperidol. Arzneimittelforschung 20:943–948
Mannens G, Huang M-L, Meuldermans W, Hendrickx J, Woestenborghs R, Heykants J (1993) Absorption, metabolism and excretion of risperidone in humans. (accepted 1993) Drug Metab Dispos
Megens AAHP, Awouters FHL, Meert TF, Schellekens KHL, Niemegeers CJE, Janssen PAJ (1992) Pharmacological profile of the new potent neuroleptic ocaperidone (R 79598). J Pharmacol Exp Ther 260:146–159
Mesotten F, Suy E, Pietquin M, Burton P, Heylen S, Gelders Y (1989) Therapeutic effect and safety of increasing doses of risperidone (R 64 766) in psychotic patients. Psychopharmacology 99:445–449
Meuldermans W, Hendrickx J, Mannens G, Lavijsen K, Janssen C, Bracke J, le Jeune L, Lauwers W, Heykants J (accepted 1993) The metabolism and excretion of risperidone after oral administration in rats and dogs. Drug Metab Dispos
Niemegeers CJE (1982) Antiemetic specificity of dopamine antagonists. Psychopharmacology 78:210–213
Niemegeers CJE, Lenaerts FM, Artois KSK, Janssen PAJ (1977) Interaction of drugs with apomorphine, tryptamine and norepinephrine. A new “in vivo” approach: the ATN test in rats. Arch Int Pharmcodyn Ther 227:238–253
Öhman R, Larsson M, Nilsson IM, Engel J, Carlsson A (1977) Neurometabolic and behavioural effects of haloperidol in relation to drug levels in serum and brain. Naunyn-Schmiedeberg's Arch Pharmacol 299:105–114
Pazos A, Cortés R, Palacios JM (1985) Quantitative autoradiographic mapping of serotonin receptors in the rat brain. II. Serotonin-2 receptors. Brain Res 346:231–249
Sunderland T, Cohen BM (1987) Blood to brain distribution of neuroleptics. Psychiatry Res 20:299–305
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van Beijsterveldt, L.E.C., Geerts, R.J.F., Leysen, J.E. et al. Regional brain distribution of risperidone and its active metabolite 9-hydroxy-risperidone in the rat. Psychopharmacology 114, 53–62 (1994). https://doi.org/10.1007/BF02245444
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DOI: https://doi.org/10.1007/BF02245444