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Titolo:
CYP1A2 activity as measured by a caffeine test predicts clozapine and active metabolite norclozapine steady-state concentration in patients with schizophrenia
Autore:
Ozdemir, V; Kalow, W; Posner, P; Collins, EJ; Kennedy, JL; Tang, BK; Albers, LJ; Reist, C; Roy, R; Walkes, W; Afra, P;
Indirizzi:
Univ Toronto, Dept Pharmacol, Toronto, ON M5S 1A8, Canada Univ Toronto Toronto ON Canada M5S 1A8 macol, Toronto, ON M5S 1A8, Canada Univ Toronto, Dept Psychiat, Toronto, ON M5S 1A8, Canada Univ Toronto Toronto ON Canada M5S 1A8 chiat, Toronto, ON M5S 1A8, Canada Ctr Addict & Mental Hlth, Neurogenet Sect, Toronto, ON, Canada Ctr Addict & Mental Hlth Toronto ON Canada net Sect, Toronto, ON, Canada Univ Calif Irvine, Dept Psychiat & Human Behav, Irvine, CA 92717 USA Univ Calif Irvine Irvine CA USA 92717 & Human Behav, Irvine, CA 92717 USA Long Beach Vet Adm Med Ctr, Irvine, CA USA Long Beach Vet Adm Med Ctr Irvine CA USA Vet Adm Med Ctr, Irvine, CA USA
Titolo Testata:
JOURNAL OF CLINICAL PSYCHOPHARMACOLOGY
fascicolo: 4, volume: 21, anno: 2001,
pagine: 398 - 407
SICI:
0271-0749(200108)21:4<398:CAAMBA>2.0.ZU;2-6
Fonte:
ISI
Lingua:
ENG
Soggetto:
MULTIPLE-DOSE PHARMACOKINETICS; TREATMENT-RESISTANT SCHIZOPHRENIA; SEROTONIN REUPTAKE INHIBITORS; N-DESMETHYLCLOZAPINE; CLINICAL-RESPONSE; IN-VITRO; SERUM LEVELS; CYTOCHROME-P450 ENZYMES; PSYCHIATRIC-PATIENTS; ANTIPSYCHOTIC AGENT;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Clinical Medicine
Life Sciences
Citazioni:
88
Recensione:
Indirizzi per estratti:
Indirizzo: Kalow, W Univ Toronto, Dept Pharmacol, Med Sci Bldg,Room 4206,1 Kings CollCircle, Toronto, ON M5S 1A8, Canada Univ Toronto Med Sci Bldg,Room 4206,1 Kings Coll Circle Toronto ON Canada M5S 1A8
Citazione:
V. Ozdemir et al., "CYP1A2 activity as measured by a caffeine test predicts clozapine and active metabolite norclozapine steady-state concentration in patients with schizophrenia", J CL PSYCH, 21(4), 2001, pp. 398-407

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 longterm 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 wasmeasured 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 ahigher clozapine (3.2-fold) and norclozapine (2.3-fold) concentration thansmokers (p < 0.05). Furthermore, there was marked person-to-person variation in CYP1A2 activity during multiple-dose clozapine treatment (coefficientof variation = 60%). Age, weight, serum creatinine, and grapefruit juice consumption did not significantly contribute to variability in clozapine andnorclozapine concentration (p > 0.05). In conclusion, CYP1A2 is one of theimportant 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 noncomplianceand high CYP1A2 activity.

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Documento generato il 27/01/20 alle ore 16:52:42