Factors affecting drug concentrations and QT interval during thioridazine therapy.
The objective of this study was to investigate factors affecting steady-state plasma concentrations of thioridazine. A cross-sectional study of patients receiving chronic thioridazine was employed. Common allelic variants of CYP2D6 and CYP2C19, as well as thioridazine and metabolite concentrations and QTc intervals, were determined. In 97 patients, dose-corrected plasma concentrations (C/Ds) of thioridazine and metabolites were correlated with age but not sex or CYP2C19 genotype. Patients with no functional CYP2D6 alleles (n=9) had significantly higher C/D for thioridazine (P=0.017) and the ring sulfoxide metabolite and a significantly higher thioridazine/mesoridazine ratio compared with those with >/=1 functional CYP2D6 allele (n=82). Smokers had significantly lower C/D for thioridazine, mesoridazine, and sulforidazine and significantly lower thioridazine/ring sulfoxide ratios than non-smokers. QTc interval was not significantly affected by CYP2D6 or CYP2C19 genotypes. Plasma concentrations of thioridazine are influenced by age, smoking, and CYP2D6 genotype, but CYP2D6 genotype does not appear to influence on-treatment QTc interval.
Thanacoody
R H K
RH
School of Clinical and Laboratory Sciences, University of Newcastle, Newcastle upon Tyne, UK.
Daly
A K
AK
Reilly
J G
JG
Ferrier
I N
IN
Thomas
S H L
SH
D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D014150:Antipsychotic Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood* / Q000493:pharmacokinetics; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics / Q000378:metabolism; D003430:Cross-Sectional Studies; D065731:Cytochrome P-450 CYP2C19; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics / Q000378:metabolism; D018492:Dopamine Antagonists / Q000009:adverse effects / Q000097:blood; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D006329:Heart Conduction System / Q000187:drug effects*; D006801:Humans; D016014:Linear Models; D008133:Long QT Syndrome / Q000097:blood / Q000139:chemically induced* / Q000503:physiopathology; D008297:Male; D008653:Mesoridazine / Q000009:adverse effects / Q000097:blood; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000235:genetics / Q000378:metabolism; D012307:Risk Factors; D012559:Schizophrenia / Q000188:drug therapy; D012737:Sex Factors; D012907:Smoking / Q000009:adverse effects; D013881:Thioridazine / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood* / Q000493:pharmacokinetics; D044465:White People / Q000235:genetics
D014150:Antipsychotic Agents; D018492:Dopamine Antagonists; D008653:Mesoridazine; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D019389:Cytochrome P-450 CYP2D6; D013881:Thioridazine