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

被引:79
作者
Özdemir, V
Kalow, W
Posner, P
Collins, EJ
Kennedy, JL
Tang, BK
Albers, LJ
Reist, C
Roy, R
Walkes, W
Afra, P
机构
[1] Univ Toronto, Dept Pharmacol, Toronto, ON M5S 1A8, Canada
[2] Univ Toronto, Dept Psychiat, Toronto, ON M5S 1A8, Canada
[3] Ctr Addict & Mental Hlth, Neurogenet Sect, Toronto, ON, Canada
[4] Univ Calif Irvine, Dept Psychiat & Human Behav, Irvine, CA 92717 USA
[5] Long Beach Vet Adm Med Ctr, Irvine, CA USA
关键词
D O I
10.1097/00004714-200108000-00007
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
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 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.
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页码:398 / 407
页数:10
相关论文
共 88 条
[71]  
Ring BJ, 1996, J PHARMACOL EXP THER, V276, P658
[72]   Flavin monooxygenase 3 (FMO3) polymorphism in a white population:: Allele frequencies, mutation linkage, and functional effects on clozapine and caffeine metabolism [J].
Sachse, C ;
Ruschen, S ;
Dettling, M ;
Schley, J ;
Bauer, S ;
Müller-Oerlinghausen, B ;
Roots, I ;
Brockmöller, J .
CLINICAL PHARMACOLOGY & THERAPEUTICS, 1999, 66 (04) :431-438
[73]   Functional significance of a C→A polymorphism in intron I of the cytochrome P450 CYP1A2 gene tested with caffeine [J].
Sachse, C ;
Brochmöller, J ;
Bauer, S ;
Roots, I .
BRITISH JOURNAL OF CLINICAL PHARMACOLOGY, 1999, 47 (04) :445-449
[74]  
Schaber G, 1998, BRIT J CLIN PHARMACO, V46, P453
[75]   Clozapine serum concentrations are lower in smoking than in non-smoking schizophrenic patients [J].
Seppälä, NH ;
Leinonen, EVJ ;
Lehtonen, ML ;
Kivistö, KT .
PHARMACOLOGY & TOXICOLOGY, 1999, 85 (05) :244-246
[76]  
SHIMADA T, 1994, J PHARMACOL EXP THER, V270, P414
[77]  
SIMPSON GM, 1978, AM J PSYCHIAT, V135, P99
[78]   THE RELATIONSHIP BETWEEN PAROXETINE AND THE SPARTEINE OXIDATION POLYMORPHISM [J].
SINDRUP, SH ;
BROSEN, K ;
GRAM, LF ;
HALLAS, J ;
SKJELBO, E ;
ALLEN, A ;
ALLEN, GD ;
COOPER, SM ;
MELLOWS, G ;
TASKER, TCG ;
ZUSSMAN, BD .
CLINICAL PHARMACOLOGY & THERAPEUTICS, 1992, 51 (03) :278-287
[79]   The epidemiology of tobacco use, dependence, and cessation in the United States [J].
Smith, SS ;
Fiore, MC .
PRIMARY CARE, 1999, 26 (03) :433-+
[80]   Pharmacokinetic analysis of felodipine-grapefruit juice interaction based on an irreversible enzyme inhibition model [J].
Takanaga, H ;
Ohnishi, A ;
Matsuo, H ;
Murakami, H ;
Sata, H ;
Kuroda, K ;
Urae, A ;
Higuchi, S ;
Sawada, Y .
BRITISH JOURNAL OF CLINICAL PHARMACOLOGY, 2000, 49 (01) :49-58