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.
Department of Pharmacology and Psychiatry, Medical School, University of Extremadura, Badajoz, Spain.
J A
JA
Carrillo
A G
AG
Herraiz
S I
SI
Ramos
J
J
Benítez
D000328:Adult; D014150:Antipsychotic Agents / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001682:Biological Availability; D001711:Biotransformation; D002110:Caffeine / Q000009:adverse effects*; D002851:Chromatography, High Pressure Liquid; D003024:Clozapine / Q000009:adverse effects / Q000031:analogs & derivatives / Q000493:pharmacokinetics* / Q000627:therapeutic use; D019388:Cytochrome P-450 CYP1A2 / Q000097:blood; D065609:Cytochrome P-450 CYP1A2 Inhibitors; D004305:Dose-Response Relationship, Drug; D016903:Drug Monitoring; D005260:Female; D006801:Humans; D008297:Male; D011569:Psychiatric Status Rating Scales; D012559:Schizophrenia / Q000175:diagnosis / Q000188:drug therapy / Q000201:enzymology*; D013375:Substance Withdrawal Syndrome / Q000175:diagnosis / Q000201:enzymology*
D014150:Antipsychotic Agents; D065609:Cytochrome P-450 CYP1A2 Inhibitors; C058272:norclozapine; D002110:Caffeine; D019388:Cytochrome P-450 CYP1A2; D003024:Clozapine