Abstract
The hydroxylation of the new antipsychotic drug risperidone to its main, active metabolite 9-hydroxyrisperidone is catalyzed by the hepatic cytochrome P450 enzyme CYP2D6, and cosegregates with the polymorphic hydroxylation of debrisoquin. We have previously examined central D2 dopamine and 5-HT2 receptor occupancy after 1 mg risperidone orally in three healthy subjects who were extensive metabolizers (EM) of debrisoquin, using positron emission tomography and the radioligands [11C]raclopride and [11C]NMSP. In this study, the same experimental design was repeated in two healthy poor metabolizers (PM) of debrisoquin to compare the D2 and 5-HT2 receptor occupancy induced by risperidone in EM and PM. The two PM had much higher plasma concentrations and longer elimination half-lives of risperidone than the three EM. Plasma concentrations of the sum of risperidone and 9-hydroxyrisperidone partly overlapped among the EM and PM. D2 receptor occupancy was 50% and 54% in the two PM, as compared to 40%, 43% and 55% in the EM. 5-HT2 receptor occupancy was 63% and 73%, as compared to 45%, 56% and 68% in the EM. These findings support the view that the active 9-hydroxyl metabolite of risperidone contributes to the in vivo effects of risperidone in humans, and thus partly counterbalances the marked variability in the disposition of risperidone.
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References
Alván G, Bechtel P, Iselius L, Gundert-Remy U (1990) Hydroxylation polymorphisms of debrisoquine and mephenytoin in European populations. Eur J Clin Pharmacol 39:533–537
Barnes TRE (1989) A rating scale for drug-induced akathisia. Br J Psychiatry 154:672–676
Dahl M-L, Johansson I, Porsmyr Palmertz M, Ingelman-Sundberg M, Sjöqvist F (1992) Analysis of the CYP2D6 gene in relation to debrisoquine hydroxylation in a Swedish population. Clin Pharmacol Ther 51:12–17
Dannals RF, Ravert HT, Wilson AA, Wagner HN Jr (1986) An improved synthesis of (3-N-[11C]methyl)spiperone. Appl Radiat Isot 37:433–434
Farde L, Pauli S, Hall H, Eriksson L, Halldin C, Högberg T, Nilsson L, Sjögren I, Stone-Elander S (1988) Stereoselective binding of11C-raclopride in living human brain — a search for extrastriatal central D2 dopamine receptors by PET. Psychopharmacology 94:471–478
Farde L, Eriksson L, Blomquist G, Halldin C (1989) Kinetic analysis of central [11C]raclopride binding to D2-dopamine receptors studied by PET — a comparison to the equilibrium analysis. J Cereb Blood Flow Metab 9:696–708
Farde L, Hall H, Pauli S, Halldin C (1995) Variability in D2 dopamine receptor density and affinity — a PET-study with [11C]raclopride in man. Synapse (in press)
Halldin C, Farde L, Högberg T, Hall H, Ström P, Ohlberger A, Solin O (1991) A comparative PET-study of five carbon-11 or fluorine-18 labelled salicylamides. Preparation and in vitro dopamine D-2 binding. Int J Rad Appl Instr B 18:871–881
Heim M, Meyer U (1990) Genotyping of poor metabolizers of debrisoquine by allele-specific PCR amplification. Lancet 336:529–532
Huang M-L, Van Peer A, Woestenborghs RJ, De Coster R, Heykants JJ, Janssen AA, Zylicz Z, Visscher HW, Jonkman JHG (1993) Pharmacokinetics of the novel antipsychotic agent risperidone and the prolactin response in healthy subjects. Clin Pharmacol Ther 54:257–268
Janssen PAJ, Niemegeers CJE, Awouters F, Schellekens KHL, Megens AAHP, Meert TF (1988) Pharmacology of risperidone (R 64766), a new antipsychotic with serotonin-S2 and dopamine-D2 antagonistic properties. J Pharmacol Exp Ther 244:685–693
Leysen JE, Gommeren W, Eens A, Chaffoy de Courcelles D de, Stoof JC, Janssen PAJ (1988) Biochemical profile of risperidone, a new antipsychotic. J Pharmacol Exp Ther 247:661–670
Mannens G, Huang ML, Meuldermans W, Hendrickx J, Woestenborghs R, Heykants J (1993) Absorption, metabolism, and excretion of risperidone in humans. Drug Metab Dispos Biol Fate Chem 21:1134–1141
Marder SR, Meilbach R (1994) Risperidone in the treatment of schizophrenia. Am J Psychiatry 151:825–835
Nyberg S, Farde L, Eriksson L, Halldin C, Eriksson B (1993) 5-HT2 and D2 dopamine receptor occupancy in the living human brain. A PET study with risperidone. Psychopharmacology 110:265–272
Sanz E, Villén T, Alm C, Bertilsson L (1989)S-Mephenytoin hydroxylation phenotypes in a Swedish population determined after coadministration with debrisoquin. Clin Pharmacol Ther 45:495–499
Simpson GM, Angus JWS (1970) A rating scale for extrapyramidal side effects. Acta Psychiatr Scand 212:11–19
Van Beijsterveldt LEC, Geerts RJF, Leysen JE, Megens AAHP, Van den Eynde HMJ, Meuldermans WEG, Heykants JJP (1994) The regional brain distribution of risperidone and its active metabolite 9-hydroxy-risperidone in the rat. Psychopharmacology 114:53–62
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Nyberg, S., Halldin, C. & Dahl, M.L. A PET study of D2 and 5-HT2 receptor occupancy induced by risperidone in poor metabolizers of debrisoquin and risperidone. Psychopharmacology 119, 345–348 (1995). https://doi.org/10.1007/BF02246302
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DOI: https://doi.org/10.1007/BF02246302