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

  • Pharmacokinetics and Disposition
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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.

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Acknowledgements

The authors wish to thank Mérida Psychiatric Hospital patients and staff, and Maria-Jesús Norberto and Macarena C. Cáceres (University of Extremadura) for their collaboration in the study. This study was supported partly by grants from the Spanish Ministerio de Sanidad y Consumo (Instituto Carlos III FIS 01/0699), Hungarian-Spanish S&T Cooperation Programme (E-45/2001), the Swedish Medical Research Council (3902), and European Union Inco-Copernicus Project (ERBIC15CT98034).

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Authors and Affiliations

  1. Department of Pharmacology and Psychiatry, Faculty of Medicine, University of Extremadura, Av. de Elvas s/n, 06071, Badajoz, Spain

    Roland Berecz, Pedro Dorado & Adrián LLerena

  2. Department of Biochemistry and Molecular Biology, University of Extremadura, Av. de Elvas s/n, 06071, Badajoz, Spain

    Pedro Fernández-Salguero

  3. Unit of Research and Clinical Psychopharmacology, Mérida Psychiatric Hospital, Spain

    Alfredo de la Rubia

  4. Department of Medical Laboratory Sciences and Technology, Karolinska Institutet, Stockholm, Sweden

    Marja-Liisa Dahl

  5. Department of Medical Sciences, Clinical Pharmacology, Uppsala University, Sweden

    Marja-Liisa Dahl

  6. Medical School, Beira Interior University, Covilhā, Portugal

    Adrián LLerena

  7. Medical and Health Science Center, Department of Psychiatry, University of Debrecen, Debrecen, Hungary

    Roland Berecz

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  1. Roland Berecz
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  6. Adrián LLerena
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Correspondence to Adrián LLerena.

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Berecz, R., de la Rubia, A., Dorado, P. et al. Thioridazine steady-state plasma concentrations are influenced by tobacco smoking and CYP2D6, but not by the CYP2C9 genotype. Eur J Clin Pharmacol 59, 45–50 (2003). https://doi.org/10.1007/s00228-003-0576-4

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