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 ra ises the hypothesis of whether caffeine withdrawal from the diet alter s the metabolism and/or clinical status of patients receiving CLZ. Sev en schizophrenic patients (six men and one woman) receiving monotherap y 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 a ssayed in plasma by high-performance liquid chromatography at three di fferent time points: A, with concomitant intake of caffeine from the d iet; B, after caffeine withdrawal for 5 days; and C, after 2 weeks of rechallenge to habitual caffeine intake. The CYP1A2 activity was deter mined 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 4 9 ng/mL (-31%) (p < 0.03), and the NOR/CLZ ratio significantly increas ed from 0.47 to 1.04 (185%) (p < 0.02). All parameters returned to ini tial figures at time point C. The NOR/CLZ ratio was significantly corr elated to the CYP1A2 index (r(s) = 0.96, p < 0.0005). In conclusion, c hanges in the habitual caffeine intake alter the metabolism of CLZ in schizophrenic patients. Thus, patient intake of caffeine should be med ically 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 estimat e of CYP1A2 activity.