Effect of thioridazine dosage on the debrisoquine hydroxylation phenotype in psychiatric patients with different CYP2D6 genotypes.
Sixteen hospitalized white European Spanish psychiatric patients treated with thioridazine alone were studied with respect to CYP2D6 genotype, debrisoquine metabolic ratio (MR), and the plasma levels of thioridazine and its metabolites mesoridazine and sulforidazine. After decreasing the dose of thioridazine the debrisoquine MR and thioridazine plasma levels were redetermined. At the initial determination (regular clinical doses, 20-300 mg/day), 14 of 16 patients (88%) were classified as poor metabolizers of debrisoquine (PMs). However, after complete withdrawal of thioridazine in 10 patients, all 10 became extensive metabolizers except two who were genotypically PMs (*4/*4). The inhibition of debrisoquine metabolism was genotype dependent. All patients with wt/wt genotype treated with a dose 150 mg/d were phenotypically PMs, all patients with wt/*4 genotype treated with a dose of 50 mg/d or greater were PMs. The debrisoquine MR from all dose changes correlated with the dose (p < 0.001) and plasma level (p < 0.001) of thioridazine. The CYP2D6 hydroxylation capacity was inhibited by thioridazine as determined by the debrisoquine MR. This inhibition was reversible by thioridazine withdrawal, and thus seems to be dose dependent and related to CYP2D6 genotype. One must consider the effects of thioridazine dosage on CYP2D6, because it may influence the metabolism of concomitant drugs or produce clinically important adverse effects such as cardiotoxicity. An awareness of this problem and cautious dosage adjustment of other drugs metabolized by the same enzyme are recommended during treatment with thioridazine.
LLerena
A
A
Department of Pharmacology, University of Extremadura, Badajoz, Spain. allerena@unex.es
Berecz
R
R
de la Rubia
A
A
Fernández-Salguero
P
P
Dorado
P
P
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014150:Antipsychotic Agents / Q000494:pharmacology*; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D003647:Debrisoquin / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005838:Genotype; D006801:Humans; D006900:Hydroxylation; D008297:Male; D001523:Mental Disorders / Q000188:drug therapy / Q000378:metabolism; D008875:Middle Aged; D013881:Thioridazine / Q000494:pharmacology*
D014150:Antipsychotic Agents; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D004791:Enzyme Inhibitors; D019389:Cytochrome P-450 CYP2D6; D013881:Thioridazine; D003647:Debrisoquin