title: CYP1A2 activity as measured by a caffeine test predicts clozapine and active metabolite steady-state concentrationin patients with schizophrenia.
abstract: Clozapine is an atypical antipsychotic drug and displays efficacy in 30% to 60% of patients with schizophrenia who do not respond to traditional antipsychotics. A clozapine concentration greater than 1,150 nmol/L increases the probability of antipsychotic efficacy. However, plasma clozapine concentration can vary more than 45-fold during long-term treatment. The aim of this study was to assess the contribution of CYP1A2 to variability in steady-state concentration of clozapine and its active metabolite norclozapine. Patients with schizophrenia or schizoaffective disorder were prospectively monitored during clozapine treatment (N = 18). The in vivo CYP1A2 activity was measured using the caffeine metabolic ratio (CMR) in overnight urine. Trough plasma samples were drawn after at least 5 days of treatment with a constant regimen of clozapine. A significant negative association was found between the CMR and the dose-corrected clozapine (r(s) = -0.87,p < 0.01) and norclozapine (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 variation in CYP1A2 activity during multiple-dose clozapine treatment (coefficient of variation = 60%). Age, weight, serum creatinine, and grapefruit juice consumption 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 treatment. Although further in vitro experiments are necessary, the precise metabolic pathways catalyzed by CYP1A2 seem to be subsequent to the formation of norclozapine, hitherto less recognized quantitatively important alternate disposition routes, or both. From a clinical perspective, an environmentally induced or constitutively high CYP1A2 expression can lead to a decrease in steady-state concentration of clozapine as well as its active metabolite norclozapine. Thus, interindividual variability in CYP1A2 activity may potentially explain treatment resistance to clozapine in some patients. CYP1A2 phenotyping with a simple caffeine test may contribute to individualization of clozapine dosage and differentiate between treat ment noncompliance and high CYP1A2 activity.
authors.affiliation: Department of Pharmacology, University of Toronto, Ontario, Canada.
authors.forename: V
authors.initials: V
authors.lastname: Ozdemir
authors.forename: W
authors.initials: W
authors.lastname: Kalow
authors.forename: P
authors.initials: P
authors.lastname: Posner
authors.forename: E J
authors.initials: EJ
authors.lastname: Collins
authors.forename: J L
authors.initials: JL
authors.lastname: Kennedy
authors.forename: B K
authors.initials: BK
authors.lastname: Tang
authors.forename: L J
authors.initials: LJ
authors.lastname: Albers
authors.forename: C
authors.initials: C
authors.lastname: Reist
authors.forename: R
authors.initials: R
authors.lastname: Roy
authors.forename: W
authors.initials: W
authors.lastname: Walkes
authors.forename: P
authors.initials: P
authors.lastname: Afra
mesh_terms: D000328:Adult; D000368:Aged; D014150:Antipsychotic Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D002110:Caffeine; D003024:Clozapine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood* / Q000493:pharmacokinetics*; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010726:Phosphodiesterase Inhibitors; D011618:Psychotic Disorders / Q000378:metabolism; D012016:Reference Values; D012559:Schizophrenia / Q000378:metabolism*; D012907:Smoking / Q000378:metabolism
chemical_list: D014150:Antipsychotic Agents; D010726:Phosphodiesterase Inhibitors; C058272:norclozapine; D002110:Caffeine; D019388:Cytochrome P-450 CYP1A2; D003024:Clozapine