Thioridazine steady-state plasma concentrations are influenced by tobacco smoking and CYP2D6, but not by the CYP2C9 genotype.
BACKGROUND
Approximately 7% of Caucasians have genetically impaired activity of the cytochrome P450 enzyme CYP2D6 and are classified as poor metabolizers (PM). The disposition of thioridazine has been related to the CYP2D6 phenotype. The present study aimed to evaluate the influence of CYP2D6 and CYP2C9 genotypes, and tobacco smoking on steady-state thioridazine plasma levels.


METHODS
Seventy-six Caucasian psychiatric patients receiving thioridazine monotherapy were studied. Debrisoquine metabolic ratio (MR) and steady-state plasma levels of thioridazine and its metabolites, mesoridazine and sulforidazine, as well as CYP2D6 (in 74 patients) and CYP2C9 (in 63 patients) genotypes were determined.


RESULTS
The median dose-corrected, steady-state plasma concentrations (C/D) of thioridazine were related to the number of functional CYP2D6 alleles ( P<0.01), being 15.2, 7.2, 4.0, 4.2 nmol/l per milligram in subjects with no, one, two, and three or more functional CYP2D6 genes, respectively. No significant differences were found in the C/Ds of mesoridazine or sulforidazine. No relationship was found between CYP2C9 genotype and plasma levels of thioridazine or its metabolites. The median C/D of thioridazine was significantly ( P<0.001) lower in smokers (4.0 nmol/l per milligram, range: 1.0-15.5; n=58) than in nonsmokers (7.4 nmol/l per milligram, range: 2.8-23.6; n=18). Also, the C/Ds of mesoridazine and sulforidazine were lower in smokers ( P<0.01). The plasma thioridazine/mesoridazine ratio significantly correlated with the debrisoquine MR ( r(2)=0.30, P<0.001).


CONCLUSIONS
The results show that the plasma concentrations of thioridazine and its metabolites are influenced by tobacco smoking and the CYP2D6 genotype, and support the dose-dependent inhibition of CYP2D6 by thioridazine. CYP2C9 does not play an important role in thioridazine metabolism.
Berecz
Roland
R
Department of Pharmacology and Psychiatry, Faculty of Medicine, University of Extremadura, Av. de Elvas s/n, 06071 Badajoz, Spain.
de la Rubia
Alfredo
A
Dorado
Pedro
P
Fernández-Salguero
Pedro
P
Dahl
Marja-Liisa
ML
LLerena
Adrián
A
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014150:Antipsychotic Agents / Q000097:blood* / Q000378:metabolism / Q000627:therapeutic use; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics* / Q000378:metabolism; D065729:Cytochrome P-450 CYP2C9; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics* / Q000378:metabolism; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D003647:Debrisoquin / Q000378:metabolism; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D011618:Psychotic Disorders / Q000188:drug therapy / Q000378:metabolism; D012907:Smoking / Q000378:metabolism*; D013881:Thioridazine / Q000097:blood* / Q000378:metabolism / Q000627:therapeutic use
D014150:Antipsychotic Agents; D065690:Cytochrome P-450 CYP2D6 Inhibitors; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; D019389:Cytochrome P-450 CYP2D6; D013881:Thioridazine; D003647:Debrisoquin