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

Eur J Clin Pharmacol. 2003 May;59(1):45-50. doi: 10.1007/s00228-003-0576-4. Epub 2003 Mar 28.


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.

Publication types

  • Clinical Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Antipsychotic Agents / blood*
  • Antipsychotic Agents / metabolism
  • Antipsychotic Agents / therapeutic use
  • Aryl Hydrocarbon Hydroxylases / genetics*
  • Aryl Hydrocarbon Hydroxylases / metabolism
  • Cytochrome P-450 CYP2C9
  • Cytochrome P-450 CYP2D6 / genetics*
  • Cytochrome P-450 CYP2D6 / metabolism
  • Cytochrome P-450 CYP2D6 Inhibitors
  • Debrisoquin / metabolism
  • Female
  • Genotype
  • Humans
  • Male
  • Middle Aged
  • Polymerase Chain Reaction
  • Psychotic Disorders / drug therapy
  • Psychotic Disorders / metabolism
  • Smoking / metabolism*
  • Thioridazine / blood*
  • Thioridazine / metabolism
  • Thioridazine / therapeutic use


  • Antipsychotic Agents
  • Cytochrome P-450 CYP2D6 Inhibitors
  • CYP2C9 protein, human
  • Cytochrome P-450 CYP2C9
  • Aryl Hydrocarbon Hydroxylases
  • Cytochrome P-450 CYP2D6
  • Thioridazine
  • Debrisoquin