Pharmacopsychiatry 2004; 37(2): 69-73
DOI: 10.1055/s-2004-815528
Original Paper
© Georg Thieme Verlag Stuttgart · New York

Relationship between Haloperidol Plasma Concentration, Debrisoquine Metabolic Ratio, CYP2D6 and CYP2C9 Genotypes in Psychiatric Patients

Adrián LLerena1 , 2 , 3 , Alfredo de la Rubia2 , Roland Berecz1 , Pedro Dorado1
  • 1Department of Pharmacology and Psychiatry, Faculty of Medicine, University of Extremadura, Badajoz, Spain
  • 2Unit of Research and Clinical Psychopharmacology, Psychiatric Hospital, Mérida
  • 3Department of Medical Sciences, Faculty of Health Sciences, University of Beira Interior, Covilhã, Portugal
This study was supported partly by a grant from the Spanish Ministry of Health, Instituto Carlos III (FIS 01/0699) and coordinated under the frame of the Hungarian-Spanish S&T Cooperation Programme (E-45/2001)
Further Information

Publication History

Received: 7.10.2002 Revised: 30.1.2003

Accepted: 26.2.2003

Publication Date:
29 March 2004 (online)

Background: Around seven percent of Caucasians are poor metabolizers of cytochrome P450, CYP2D6 due to genetically impaired activity of the enzyme. Haloperidol in vitro and in vivo inhibits the activity of CYP2D6 and also the involvement of the enzyme in haloperidol metabolism has been reported. The present study was aimed to evaluate the possible inhibition of CYP2D6 during haloperidol treatment, and to determine the effect of CYP2D6 and CYP2C9 genotypes on the plasma concentration of haloperidol. Methods: Thirty Caucasian psychiatric patients under haloperidol monotherapy were studied. CYP2D6 activity was evaluated by the debrisoquine metabolic ratio (MR), subjects with MR > 12.6 were named as poor metabolizers. Haloperidol plasma concentration was determined by high performance liquid chromatography. Results: The number of patients with debrisoquine MR > 12.6 was higher than the expected comparing to healthy volunteers (13 % vs. 6.6 %, respectively). Debrisoquine MR was correlated with the dose of haloperidol (r = 0.40, p < 0.05), and also with the plasma concentration (r = 0.58, p < 0.001). Additionally, three patients comedicated with inhibitors of CYP2D6 were studied, all of them had a debrisoquine MR > 12.6, however only one was genetically poor metabolizer of CYP2D6. CYP2D6 and CYP2C9 genotypes were not related to the dose or plasma concentration of haloperidol. Conclusions: The present data support the dose-dependent inhibitory effect of haloperidol on CYP2D6, and the influence of this enzyme activity on haloperidol plasma concentration under steady-state conditions. The inhibitory effect of haloperidol on CYP2D6 enzyme activity may result in drug interactions and unexpected high plasma concentrations when drugs metabolized by the same enzyme are given concomitantly with haloperidol.

References

  • 1 Avenoso A, Spina E, Campo G, Facciola G, Ferlito M, Zuccaro P ,. et al . Interaction between fluoxetine and haloperidol: Pharmacokinetic and clinical implications.  Pharmacol Res. 1997;  35 335-339
  • 2 Benítez J, LLerena A, Cobaleda J. Debrisoquine oxidation polymorphism in a Spanish population.  Clin Pharmacol Ther. 1988;  44 74-77
  • 3 Berecz R, LLerena A, De La Rubia A, Gómez J, Kellermann M, Dorado P ,. et al . Relationship between risperidone and 9-hydroxy-risperidone plasma concentrations and CYP2D6 enzyme activity in psychiatric patients.  Pharmacopsychiatry. 2002;  35 231-234
  • 4 Dahl M L. Cytochrome P450 phenotyping/genotyping in patients receiving antipsychotics.  Clin Pharmakokinet. 2002;  41 453-470
  • 5 Dorado P, Norberto M, Berecz R, Martínez M, de la Rubia A, Yasar Ü ,. et al . CYP2C9 genotype and diclofenac hydroxylation in a Spanish population.  Pharmacol Toxicol. 2001;  89 Suppl 1 102
  • 6 Goff D C, Midha K K, Brotman A W, Waites M, Baldessarini R J. Elevation of plasma concentrations of haloperidol after the addition of fluoxetine.  Am J Psychiatry. 1991;  148 790-792
  • 7 Gram L F, Debruyne D, Caillard V, Boulenger J P, Lacotte J, Moulin M ,. et al . Substantial rise in sparteine metabolic ratio during haloperidol treatment.  Br J Clin Pharmacol. 1989;  27 272-275
  • 8 Inaba T, Jurima M, Mahon W A, Kalow W. In vitro inhibition studies of two isozymes of human liver cytochrome P-450. Mephenytoin p-hydroxylase and sparteine monooxygenase.  Drug Metab Dispos. 1985;  13 443-448
  • 9 Kohnke M D, Griese E U, Stosser D, Gaertner I, Barth G. Cytochrome P450 2D6 deficiency and its clinical relevance in a patient treated with risperidone.  Pharmacopsychiatry. 2002;  35 116-118
  • 10 Kudo S, Ishizaki T. Pharmacokinetics of haloperidol: an update.  Clin Pharmacokinet. 1999;  37 435-456
  • 11 Ledesma M C, Agúndez J AG, Lozano L, LLerena A, Benítez J. The CYP2D6 polymorphism is not a relevant factor on steady-state haloperidol plasma levels. Abstract to Clinical Pharmacology in Psychiatry Conference. Badajoz; 1997. October 23 - 25
  • 12 LLerena A. Metabolización hepática de fármacos: Interacciones genético-ambientales en el fenotipo de debrisoquina. Doctoral Thesis. University of Extremadura Badajoz. Spain; 1988
  • 13 LLerena A, Alm C, Dahl M -L, Ekqvist B, Bertilsson L. Haloperidol disposition is dependent on debrisoquine hydroxylation phenotype.  Ther Drug Monit. 1992;  14 92-97
  • 14 LLerena A, Dahl M L, Ekqvist B, Bertilsson L. Haloperidol disposition is dependent on the debrisoquine hydroxylation phenotype: Increased plasma levels of the reduced metabolite in poor metabolizers.  Therapeutic Drug Monitoring. 1992;  14 261-264
  • 15 LLerena A, Herraiz A G, Cobaleda J, Johansson I, Dahl M -L. Debrisoquin and mephenytoin hydroxylation phenotypes and CYP2D6 genotype in patients treated with neuroleptic and antidepressant agents.  Clin Pharmacol Ther. 1993;  54 606-611
  • 16 LLerena A, Cobaleda J, Martínez C, Benítez J. Interethnic differences in drug metabolism: influence of sex-related and environmental factors on debrisoquine hydroxylation phenotype.  Eur J Drug Metab Pharmacokinet. 1996;  21 129-138
  • 17 LLerena A, Berecz R, de la Rubia A, Dorado P. QTc interval lengthening and debrisoquine metabolic ratio in psychiatric patients treated with oral haloperidol monotherapy.  European Journal of Clinical Pharmacology. 2002a ;  58 223-224
  • 18 LLerena A, Berecz R, de la Rubia A, Dorado P. QTc interval lengthening is related to CYP2D6 hydroxylation capacity and plasma concentration of thioridazine in patients.  J Psychopharmacol.. 2002b;  16 359-362
  • 19 Mahr G C, Berchou R, Balon R. A grand mal seizure associated with desipramine and haloperidol.  Can J Psychiatry. 1987;  32 463-464
  • 20 Miners J O, Birkett D J. Cytochrome P4502C9: an enzyme of major importance in human drug metabolism.  Br J Clin Pharmacol. 1998;  45 525-538
  • 21 Müller-Siecheneder F, Müller M J, Hillert A, Szegedi A, Wetzel H, Benkert O. Risperidone versus haloperidol and amitriptyline in the treatment of patients with a combined psychotic and depressive syndrome.  J Clin Psychopharmacol. 1998;  18 111-120
  • 22 Pan L, Vander Stichele R, Rosseel M T, Berlo J A, De Schepper N, Belpaire F M. Effects of smoking, CYP2D6 genotype, and concomitant drug intake on the steady state plasma concentrations of haloperidol and reduced haloperidol in schizophrenic inpatients.  Ther Drug Monit. 1999;  21 489-497
  • 23 Roh H K, Chung J Y, Oh D Y, Park C S, Svensson J O, Dahl M L,. et al . Plasma concentrations of haloperidol are related to CYP2D6 genotype at low, but not high doses of haloperidol in Korean schizophrenic patients.  Br J Clin Pharmacol. 2001;  52 265-271
  • 24 Shin J G, Kane K, Flockhart D A. Potent inhibition of CYP2D6 by haloperidol metabolites: stereoselective inhibition by reduced haloperidol.  Br J Clin Pharmacol. 2001;  51 45-52
  • 25 Stormer E, Brockmoller J, Roots I, Schmider J. Cytochrome P-450 enzymes and FMO3 contribute to the disposition of the antipsychotic drug perazine in vitro.  Psychopharmacology (Berl). 2000;  151 312-320
  • 26 Syvalahti E K, Lindberg R, Kallio J, De Vocht M. Inhibitory effects of neuroleptics on debrisoquine oxidation in man.  Br J Clin Pharmacol. 1986;  22 89-92
  • 27 Ulrich S, Neuhof S, Braun V, Meyer F P. Therapeutic window of serum haloperidol concentration in acute schizophrenia and schizoaffective disorder.  Pharmacopsychiatry. 1998;  31 163-169
  • 28 Vandel S, Bertschy G, Baumann P, Bouquet S, Bonin B, Francois T ,. et al . Fluvoxamine and fluoxetine: interaction studies with amitriptyline, clomipramine and neuroleptics in phenotyped patients.  Pharmacol Res. 1995;  31 347-353
  • 29 Yasar Ü, Eliasson E, Dahl M L, Johansson I, Ingelman-Sundberg M, Sjöqvist F. Validation of methods for CYP2C9 genotyping: frequencies of mutant alleles in a Swedish population. Biochem Biophys Res Commun 1999; 254 : 628 - 631.  Erratum in: Biochem Biophys Res Commun. 1999;  258 227
  • 30 Young D, Midha K K, Fossler M J, Hawes E M, Hubbard J W, McKay G ,. et al . Effect of quinidine on the interconversion kinetics between haloperidol and reduced haloperidol in humans: implications for the involvement of cytochrome P450IID6.  Eur J Clin Pharmacol. 1993;  44 433-438

Dr. Adrián LLerena

Faculty of Medicine

University of Extremadura

Av. de Elvas s/n

E-06071 Badajoz (Spain)

Phone: +34 924 289467

Fax: +34 924 289467

Email: allerena@unex.es