QTc Interval,CYP2D6 and CYP2C9 Genotypes and Risperidone Plasma Concentrations

Abstract

The role of certain drug metabolizing enzymes in cardiotoxicity, such as CYP2D6 for thioridazine, has been suggested. Risperidone has been shown to inhibit the delayed rectifier leading to lengthening of cardiac repolarization. The heart-rate corrected QT (QTc) interval lengthening has been reported in psychiatric patients receiving risperidone under steady-state conditions. CYP2D6 is involved in the metabolism of risperidone to 9-hydroxy (OH)-risperidone. CYP2C9 enzyme is also involved in the metabolism of several psychotropic drugs, although there are no data about its implication in risperidone metabolism. The present study aimed to evaluate the influence of CYP2D6 and CYP2C9 genotypes, and plasma concentrations of risperidone and 9-OH-risperidone on the QTc interval in patients under steady-state conditions. The relevance of CYP2D6 and CYP2C9 genotypes on risperidone metabolism was also analysed. Thirty-five White European psychiatric patients receiving risperidone monotherapy were studied. QTc interval was longer (p < 0.05) in subjects with one active CYP2D6 gene compared to those with two. The number of CYP2D6 active genes was related to the dose-corrected plasma concentration of risperidone (p < 0.05), the active moiety (risperidone plus 9-OH-risperidone) (p < 0.05) and the risperidone/9-OH-risperidone ratio (p < 0.05). CYP2C9genotypes were not related to plasma concentrations of risperidone or 9-OH-risperidone, nor QTc interval. The results suggest that CYP2D6, but not CYP2C9, may be related to QTc lengthening during treatment with risperidone. The effect of the CYP2D6 genotype in risperidone metabolism is also shown.

Keywords

CYP2D6 CYP2C9 9-hydroxy-risperidone QTc risperidone

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References

Ben-David J , Zipes D P (1993) Torsades de pointes and proarrhythmia . Lancet 341: 1578-1582

Berecz R , Llerena A , De la Rubia A , Gómez J , Kellermann M , Dorado P , Degrell I (2002) Relationship between risperidone and 9-hydroxy-risperidone plasma concentrations and CYP2D6 enzyme activity in psychiatric patients . Pharmacopsychiatry 35: 231-234

Bork J A , Rogers T , Wedlund P J , de Leon J (1999) A pilot study on risperi-done metabolism: the role of cytochromes P450 2D6 and 3A . J Clin Psychiatry 60: 469-476

Brown K , Levy H , Brenner C , Leffler S , Hamburg E L (1993) Overdose of risperidone . Ann Emerg Med 22: 1908-1910

Dorado P , Berecz R , Norberto M-J , Yasar Ü , Dahl M-L , Llerena A (2003) CYP2C9 genotypes and diclofenac metabolism in Spanish healthy volunteers . Eur J Clin Pharmacol 59: 221-225

Drolet B , Yang T , Daleau P , Roden D M , Turgeon J (2003) Risperidone prolongs cardiac repolarization by blocking the rapid component of the delayed rectifier potassium current . J Cardiovasc Pharmacol 41: 934-937

Fang J , Bourin M , Baker G B (1999) Metabolism of risperidone to 9-hydroxyrisperidone by human cytochromes P450 2D6 and 3A4 . Naunyn-Schmiedeberg’s Arch Pharmacol 359: 147-151

Gluais P , Bastide M , Caron J , Adamantidis M (2002) Risperidone prolongs cardiac action potential through reduction of K(+) currents in rabbit myocytes . Eur J Pharmacol 444: 123-132

Goldstein J A (2001) Clinical relevance of genetic polymorphisms in the human CYP2C subfamily . Br J Clin Pharmacol 52: 349-355

10.

Gury C , Canceil O , Iaria P (2000) Antipsychotic drugs and cardiovascular safety: current studies of prolonged QT interval and risk of ventricular arrhythmia . Encephale 26: 62-72

11.

[simultaneously published in Cardiovasc Res 47: 219-233 ]

12.

Huang M L , Van Peer A , Woestenborghs R , De Coster R , Heykants J , Jansen A A , Zylicz Z , Visscher H W , Jonkman J H (1993) Pharmacokinetics of the novel antipsychotic agent risperidone and the prolactin response in healthy subjects . Clin Pharmacol Ther 54: 257-268

13.

Jover F , Cuadrado J M , Andreu L , Merino J (2002) Reversible coma caused by risperidone-ritonavir interaction Clin Neuropharmacol 25: 251-253

14.

Kohnke M D , Griese E U , Stosser D , Gaertner I , Barth G (2002) Cytochrome P450 2D6 deficiency and its clinical relevance in a patient treated with risperidone . Pharmacopsychiatry 35: 116-118

15.

Kongsamut S , Kang J , Chen X L , Roehr J , Rampe D (2002) A comparison of the receptor binding and HERG channel affinities for a series of antipsychotic drugs . Eur J Pharmacol 450: 37-41

16.

Kopala L C , Day C , Dillman B , Gardner D (1998) A case of risperidone overdose in early schizophrenia: a review of potential complications . J Psychiatry Neurosci 23: 305-308

17.

Lee C R , Goldstein J A , Pieper J A (2002) Cytochrome P450 2C9 polymorphisms: a comprehensive review of the in-vitro and human data . Pharmacogenetics 12: 251-263

18.

Llerena A , Cobaleda J , Martínez C , Benítez J (1996) Interethnic differences in drug metabolism: influence of genetic and environmental factors on debrisoquine hydroxylation phenotype . Eur J Drug Metab Pharmacokinet 21: 129-138

19.

Llerena A , Berecz R , de la Rubia A , Fernández-Salguero P , Dorado P (2001) Effect of thioridazine dosage on the debrisoquine hydroxylation phenotype in psychiatric patients with different CYP2D6 genotypes . Ther Drug Monit 14: 616-620

20.

Llerena A , Berecz R , de la Rubia A , Dorado P (2002a) QTc interval lengthening and debrisoquine metabolic ratio in psychiatric patients treated with oral haloperidol monotherapy . Eur J Clin Pharmacol 58: 223-224

21.

Llerena A , Berecz R , de la Rubia A , Dorado P (2002b) QTc interval lengthening is related to CYP2D6 hydroxylation capacity and plasma concentration of thioridazine in patients . J Psychopharmacol 16: 359-362

22.

Llerena A , Berecz R , Dorado P , De la Garza C S , Norberto M J , Cáceres M , Gutierrez J R (2003) Determination of risperidone and 9-hydroxyrisperidone in human plasma by liquid chromatography: application to the evaluation of CYP2D6 drug interactions . J Chromatogr B 783: 213-219

23.

Leysen J E , Janssen P M , Megens A A , Schotte A (1994) Risperidone: a novel antipsychotic with balanced serotonin-dopamine antagonism, receptor occupancy profile, and pharmacologic activity . J Clin Psychiatry 55 (Suppl): 5-12

24.

Lo Vecchio F , Hamilton R J , Hoffman R J (1996) Risperidone overdose . Am J Emerg Med 14: 95-96

25.

Magyar J , Bányász T , Bagi Z , Pacher P , Szentandrássy N , Fülöp L , Kecskeméti V , Nánási P P (2002) Electrophysiological effects of risperidone in mammalian cardiac cells . Naunyn-Schmiedeberg’s Arch Pharmacol 366: 350-356

26.

Mannens G , Huang M L , Meuldermans W , Hendrickx J , Woestenborghs R , Heykants J (1993) Absorption, metabolism, and excretion of risperidone in humans . Drug Metab Dispos 21: 1134-1141

27.

Ravin D S , Levenson J W (1997) Fatal cardiac event following initiation of risperidone therapy . Ann Pharmacother 31: 867-870

28.

Ray W A , Meredith S , Thapa P B , Meador K G , Hall K , Murray K T (2001) Antipsychotics and the risk of sudden cardiac death . Arch Gen Psychiatry 58: 1161-1167

29.

Reilly J G , Ayis S A , Ferrier I N , Jones S J , Thomas S H (2000) QTc-interval abnormalities and psychotropic drug therapy in psychiatric patients . Lancet 355: 1048-1052

30.

Schouten E G , Dekker J M , Meppelink P , Kok F J , Vandenbroucke J P , Pool J (1991) QT interval prolongation predicts cardiovascular mortality in an apparently healthy population . Circulation 84: 1516-1523

31.

Scordo M G , Spina E , Facciola G , Avenoso A , Johansson I , Dahl M L (1999) Cytochrome P450 2D6 genotype and steady state plasma levels of risperidone and 9-hydroxyrisperidone . Psychopharmacology 147: 300-305

32.

Spina E , Avenoso A , Scordo M G , Ancione M , Madia A , Gatti G , Perucca E (2002) Inhibition of risperidone metabolism by fluoxetine in patients with schizophrenia: a clinically relevant pharmacokinetic drug interaction . J Clin Psychopharmacol 22: 419-423

33.

Stormer E , Brockmoller J , Roots I , Schmider J (2000) Cytochrome P-450 enzymes and FMO3 contribute to the disposition of the antipsychotic drug perazine in vitro . Psychopharmacology (Berl) 151: 312-320

34.

Study 054. Briefing document for Zeldox capsules (ziprasidone HCl) FDA Psychopharmacological Drugs Advisory Committee, 19 July 2000 [available at http://www.fda.gov/ohrms/dockets/ac/00/backgrd/3619b1a.pdf; accessed 12 February 2003]

35.

Zarate C A Jr , Baldessarini R J , Siegel A J , Nakamura A , McDonald J , Muir-Hutchinson L A , Cherkerzian T , Tohen M (1997) Risperidone in the elderly: a pharmacoepidemiologic study . J Clin Psychiatry 58: 311-317