Ozdemir V, Kalow W, Posner P, Collins E J, Kennedy J L, Tang B K, Albers L J, Reist C, Roy R, Walkes W, Afra P
Department of Pharmacology, University of Toronto, Ontario, Canada.
J Clin Psychopharmacol. 2001 Aug;21(4):398-407. doi: 10.1097/00004714-200108000-00007.
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.
氯氮平是一种非典型抗精神病药物，在30%至60%对传统抗精神病药物无反应的精神分裂症患者中显示出疗效。氯氮平浓度大于1150 nmol/L会增加抗精神病疗效的可能性。然而，在长期治疗期间，血浆氯氮平浓度的变化可能超过45倍。本研究的目的是评估CYP1A2对氯氮平及其活性代谢物去甲氯氮平稳态浓度变异性的影响。在氯氮平治疗期间对精神分裂症或分裂情感性障碍患者进行前瞻性监测（N = 18）。使用过夜尿液中的咖啡因代谢率（CMR）测量体内CYP1A2活性。在用恒定剂量的氯氮平治疗至少5天后采集谷值血浆样本。发现CMR与剂量校正后的氯氮平（r(s)= -0.87，p < 0.01）和去甲氯氮平（r(s)= -0.76，p < 0.01）浓度之间存在显著负相关。非吸烟者的氯氮平（3.2倍）和去甲氯氮平（2.3倍）浓度高于吸烟者（p < 0.05）。此外，在多剂量氯氮平治疗期间，CYP1A2活性存在明显的个体差异（变异系数 = 60%）。年龄、体重、血清肌酐和葡萄柚汁摄入量对氯氮平和去甲氯氮平浓度的变异性没有显著影响（p > 0.05）。总之，CYP1A2是多剂量治疗期间氯氮平处置的重要影响因素之一。尽管需要进一步的体外实验，但CYP1A2催化的精确代谢途径似乎在去甲氯氮平形成之后，去甲氯氮平是迄今尚未被充分认识到的在数量上重要的替代处置途径，或者两者皆是。从临床角度来看，环境诱导或固有高表达的CYP1A2可导致氯氮平及其活性代谢物去甲氯氮平的稳态浓度降低。因此，CYP1A2活性的个体差异可能潜在地解释了一些患者对氯氮平治疗的抵抗性。用简单的咖啡因试验进行CYP1A2表型分析可能有助于氯氮平剂量的个体化，并区分治疗不依从和高CYP1A2活性。
