Pharmacokinetic interaction of fluvoxamine and thioridazine in schizophrenic patients.

This study investigated to what extent fluvoxamine affects the pharmacokinetics of thioridazine (THD) in schizophrenic patients under steady-state conditions. Concentrations of THD, mesoridazine, and sulforidazine were measured in plasma samples obtained from 10 male inpatients, aged 36 to 78 years, at three different time points: A, during habitual monotherapy with THD at 88 +/-54 mg/day; B, after addition of a low dosage of fluvoxamine (25 mg twice a day) for 1 week; and C, 2 weeks after fluvoxamine discontinuation. After the addition of fluvoxamine, THD concentrations relative to time point A significantly increased approximately threefold from 0.40 to 1.21 micromol/L (225%) (p < 0.002), mesoridazine concentrations increased from 0.65 to 2.0 micromol/L (219%) (p < 0.004), and sulforidazine levels increased from 0.21 to 0.56 micromol/L (258%) (p < 0.004). The THD-mesoridazine and THD-sulforidazine ratios remained unchanged during the study. Mean plasma THD, mesoridazine, and sulforidazine levels decreased at time point C, but despite fluvoxamine discontinuation for 2 weeks, three patients continued to exhibit elevated concentrations of THD and its metabolites. In conclusion, fluvoxamine markedly interferes with the metabolism of THD, probably at the CYP2C19 and/or CYP1A2 enzyme level. Therefore, clinicians should be aware of the potential for a clinical drug interaction between both compounds, and careful monitoring of THD levels is valuable to prevent the accumulation of the drug and resulting toxicity.

Effects of caffeine withdrawal from the diet on the metabolism of clozapine in schizophrenic patients.

Both clozapine (CLZ) and caffeine are CYP1A2 substrates. This study raises the hypothesis of whether caffeine withdrawal from the diet alters the metabolism and/or clinical status of patients receiving CLZ. Seven schizophrenic patients (six men and one woman) receiving monotherapy with CLZ at 271+/-102 mg/day (3.73+/-1.4 mg/kg) participated in the study. CLZ, norclozapine (NOR), and clozapine-N-oxide (NOX) were assayed in plasma by high-performance liquid chromatography at three different time points: A, with concomitant intake of caffeine from the diet; B, after caffeine withdrawal for 5 days; and C, after 2 weeks of rechallenge to habitual caffeine intake. The CYP1A2 activity was determined by means of a urinary caffeine test. After a caffeine-free diet for 5 days, CLZ concentrations relative to time point A decreased from 486 to 306 ng/mL (-47%) (p < 0.02), NOX levels decreased from 66 to 49 ng/mL (-31%) (p < 0.03), and the NOR/CLZ ratio significantly increased from 0.47 to 1.04 (185%) (p < 0.02). All parameters returned to initial figures at time point C. The NOR/CLZ ratio was significantly correlated to the CYP1A2 index (rs = 0.96, p < 0.0005). In conclusion, changes in the habitual caffeine intake alter the metabolism of CLZ in schizophrenic patients. Thus, patient intake of caffeine should be medically supervised, and the monitoring of CLZ and metabolite levels may be warranted. Furthermore, in those patients who receive therapy with CLZ, the NOR/CLZ ratio may provide an additional and valuable estimate of CYP1A2 activity.

Debrisoquin and mephenytoin hydroxylation phenotypes and CYP2D6 genotype in patients treated with neuroleptic and antidepressant agents.

Debrisoquin and S-mephenytoin hydroxylation phenotypes were determined in 72 Spanish psychiatric patients treated with neuroleptic or antidepressant agents. One patient (1.4%) was classified as a poor metabolizer of S-mephenytoin. Between both neuroleptic- and antidepressant-treated patients, the distribution of the debrisoquin metabolic ratio was shifted toward higher values compared with 54 drug-free healthy subjects. Forty percent of patients treated with neuroleptics and 5% of patients treated with antidepressants were classified as poor metabolizers of debrisoquin. CYP2D6 genotype analysis in 36 neuroleptic-treated patients confirmed that the high metabolic ratios were attributable to inhibition of CYP2D6 and not to overrepresentation of subjects with poor metabolizer genotypes. In 48 selected Spanish drug-free subjects, CYP2D6 genotype predicted the phenotype with 95% accuracy. Neuroleptics and antidepressants interfere at therapeutic doses with phenotyping for CYP2D6 but not for S-mephenytoin hydroxylation capacity. In psychotropic-treated patients, genotyping provides a valuable tool for prediction of the CYP2D6 phenotype.