CYP1A2 activity as measured by a caffeine test predicts clozapine and active metabolite norclozapine steady-state concentration in patients with schizophrenia

Clozapine is an atypical antipsychotic drug and displays efficacy in 30% to 60% of patients with schizophrenia who do not respond to traditional antip sychotics. A clozapine concentration greater than 1,150 nmol/L increases th e probability of antipsychotic efficacy. However, plasma clozapine concentr ation can vary more than 45-fold during longterm treatment. The aim of this study was to assess the contribution of CYP1A2 to variability in steady-st ate concentration of clozapine and its active metabolite norclozapine. Pati ents with schizophrenia or schizoaffective disorder were prospectively moni tored during clozapine treatment (N = 18). The in vivo CYP1A2 activity was measured using the caffeine metabolic ratio (CMR) in overnight urine. Troug h plasma samples were drawn after at least 5 days of treatment with a, cons tant regimen of clozapine. A significant negative association was found bet ween the CMR and the dose-corrected clozapine (r(s) = -0.87,p < 0.01) and n orclozapine (r(s) = -0.76,p < 0.01) concentrations. Nonsmokers displayed a higher clozapine (3.2-fold) and norclozapine (2.3-fold) concentration than smokers (p < 0.05). Furthermore, there was marked person-to-person variatio n in CYP1A2 activity during multiple-dose clozapine treatment (coefficient of variation = 60%). Age, weight, serum creatinine, and grapefruit juice co nsumption did not significantly contribute to variability in clozapine and norclozapine concentration (p > 0.05). In conclusion, CYP1A2 is one of the important contributors to disposition of clozapine during multiple-dose tre atment. Although further in vitro experiments are necessary, the precise me tabolic pathways catalyzed by CYP1A2 seem to be subsequent to the formation of norclozapine, hitherto less recognized quantitatively important alterna te disposition routes, or both. From a clinical perspective, an environment ally induced or constitutively high CYP1A2 expression can lead to a decreas e in steady-state concentration of clozapine as well as its active metaboli te norclozapine. Thus, interindividual variability in CYP1A2 activity may p otentially explain treatment resistance to clozapine in some patients. CYP1 A2 phenotyping with a simple caffeine test may contribute to individualizat ion of clozapine dosage and differentiate between treat ment noncompliance and high CYP1A2 activity.