Thioridazine steady-state plasma concentrations are influenced by tobacco smoking and CYP2D6, but not by the CYP2C9 genotype

Abstract

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).

Conclusion: 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.