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Factors affecting drug concentrations and QT interval during thioridazine therapy
R H K Thanacoody1, A K Daly, J G Reilly
1School of Clinical and Laboratory Sciences, University of Newcastle, Newcastle upon Tyne, UK.
Clinical Pharmacology and Therapeutics
|April 27, 2007
Summary
Steady-state thioridazine plasma concentrations are influenced by age, smoking, and CYP2D6 genotype. However, CYP2D6 genotype did not significantly affect the QTc interval in patients on this medication.
Area of Science:
- Pharmacogenetics
- Clinical Pharmacology
- Psychiatric Drug Metabolism
Background:
- Thioridazine is an antipsychotic medication with variable plasma concentrations.
- Cytochrome P450 enzymes, specifically CYP2D6 and CYP2C19, are involved in thioridazine metabolism.
- Understanding factors influencing thioridazine levels is crucial for optimizing treatment and minimizing adverse effects.
Purpose of the Study:
- To investigate the impact of genetic variations (CYP2D6, CYP2C19), age, and smoking status on steady-state plasma concentrations of thioridazine and its metabolites.
- To assess the relationship between CYP2D6 and CYP2C19 genotypes and QTc interval prolongation in patients receiving chronic thioridazine therapy.
Main Methods:
- A cross-sectional study involving 97 patients on chronic thioridazine treatment.
- Measurement of thioridazine and metabolite plasma concentrations, CYP2D6 and CYP2C19 genotyping, and QTc interval assessment.
- Statistical analysis to correlate dose-corrected plasma concentrations (C/Ds) and QTc intervals with demographic and genetic factors.
Main Results:
- Dose-corrected thioridazine and metabolite concentrations (C/Ds) correlated with age but not sex or CYP2C19 genotype.
- Patients with no functional CYP2D6 alleles exhibited significantly higher thioridazine C/Ds and thioridazine/mesoridazine ratios compared to those with functional alleles (P=0.017).
- Smokers showed significantly lower C/Ds for thioridazine and its metabolites, and lower thioridazine/ring sulfoxide ratios than non-smokers.
Conclusions:
- Plasma concentrations of thioridazine are significantly influenced by age, smoking status, and CYP2D6 genotype.
- CYP2D6 genotype does not appear to influence the on-treatment QTc interval in patients taking thioridazine.
- These findings highlight the importance of pharmacogenetic and lifestyle factors in thioridazine therapy management.
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