Relevance of CYP2D6-1584C>G polymorphism for thioridazine:mesoridazine plasma concentration ratio in psychiatric patients

Abstract

Aims: The CYP2D6 -1584C>G (rs1080985) polymorphism has been identified as another major factor for CYP2D6 function that is possibly associated with ultrarapid metabolism. The mutant -1584G promoter genotype seems to be consistently related to a higher protein expression than -1584C. However, the impact this SNP in the CYP2D6 promoter region has on plasma levels of patients taking CYP2D6 substrates, such as thioridazine, has not been studied. Previously, we showed the validity of the mesoridazine:thioridazine ratio to assess CYP2D6 activity in clinical settings. Therefore, the aim of this study was to analyze the relationship between the presence of the CYP2D6 -1584C>G polymorphism and the plasma concentrations of thioridazine and its metabolites in a previously studied population of patients in order to evaluate the implications for CYP2D6 hydroxylation capacity. Materials & methods: The CYP2D6 -1584C>G polymorphism was determined by using a PCR-RFLP method in 61 Caucasian psychiatric patients receiving thioridazine monotherapy. Results: Among patients with two active CYP2D6 genes, there were significant differences in the thioridazine:mesoridazine plasma concentrations ratio (p < 0.05) among the three CYP2D6 -1584C>G genotype groups. Moreover, in this group of patients the thioridazine:mesoridazine ratio was lower (p < 0.05) in carriers of CYP2D6 -1584G allele than in patients homozygous for CYP2D6 -1584C allele. However, no differences in thioridazine or its metabolite concentrations between homozygous CYP2D6 -1584C allele carriers and carriers of the -1584G allele were found. Conclusion: According to the present results the concentration ratio of thioridazine to mesoridazine was related to the CYP2D6 -1584C>G polymorphism. It is likely that individuals who carry CYP2D6 -1584G versus homozygotes for the -1584C allele may present an increased CYP2D6 activity.