Original Paper	Pharmacopsychiatry 2004; 37: 69-73 DOI: 10.1055/s-2004-815528
© 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
1 Department of Pharmacology and Psychiatry, Faculty of Medicine, University of Extremadura, Badajoz, Spain 2 Unit of Research and Clinical Psychopharmacology, Psychiatric Hospital, Mérida 3 Department 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)

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.