CYP1 A2在体内氯氮平去甲基代谢中的作用  

CLOZAPINE DEMETHYLATION COVARIES WITH CYP1A2 ACTIVITY DETERMINED BY A CAFFEINE TEST

作　　者：王传跃[1] 周宏灏[1] 杨德森[1] 陈远光[1] 赵靖平[1] 许振华[2] 欧阳东生 朱荣华[1] 

机构地区：[1]湖南医科大学精神卫生研究所,长沙410011 [2]湖南医科大学遗传药理学研究所,长沙410008

出　　处：《中国临床药理学杂志》1999年第5期365-368,共4页The Chinese Journal of Clinical Pharmacology

摘　　要：通过检测咖啡因及其代谢产物 ,探讨细胞色素P450 酶的亚型1A2(CYP1A2)在体内氯氮平去甲基代谢中的作用。9例男性健康志愿者口服单剂咖啡因150mg ,5h时采取血样和尿样 ,咖啡因代谢产物与咖啡因的比值反映CYP1A2活性。两天后单剂氯氮平10mg,收集0～24h尿和药代动力学设计的血样。0～24h尿中氯氮平剩余量占给药剂量的百分率(CLZ %dose)以及氯氮平0～24h药时曲线下面积(AUC0→24)可以反映氯氮平清除 ;0～24h尿中去甲氯氮平生成量占氯氮平给药剂量的百分率(DCLZ %dose)以及去甲氯氮平AUC0→24 可以反映去甲氯氮平生成。结果显示 ,血清咖啡因代谢比值(17X/137X)与尿中氯氮平清除率CLZ %dose(r= -0.2032,P>0.05)无显著相关 ,与尿中去甲氯氮平生成率DCLZ %dose(r=0.6824,P<0.05)正相关 ;血清咖啡因代谢比值还与氯氮平AUC0→24 的倒数(r=0.8098,P<0.01)以及去甲氯氮平AUC0→24 (r=0.7525,P<0.05)正相关。尿中咖啡因代谢比值[(17X +17U)/137X]与氯氮平AUC0→24的倒数(r=0.6982,P<0.05)以及去甲氯氮平AUC0→24(r=0.8480,P<0.01)正相关。本研究通过酶活性相关实验证实CYP1A2在体内氯氮平的清除及其去甲基代谢产物的生成上起作用。临床上合用其他影响CYP1A2活性的药物时需密切监测氯氮平血浓度。The aim of these studies was to investigate the relationship between clozapine demethylation and CYP1A2 enzyme activities by a caffeine test in vivo. Nine male volunteers were enrolled in the study. 150 mg caffeine was taken as a single oral dose. The blood and urine samples were collected at 5th hour after administration of caffeine. After a washout period of 2 days, they received a single oral dose of clozapine 10 mg. Clozapine elimination was assessed by the percentage of the dose of clozapine excreted as the drug in urine (CLZ%dose) and by clozapine AUC0→24. The formation of desmethylclozapine was assessed by the percentage of the dose of clozapine excreted as desmethylclozapine in urine (DCLZ%dose) and by desmethylclozapine AUC0→24. The ratios of caffeine metabolism in serum, paraxanthine/caffeine, were correlated with DCLZ%dose (n=9, r=0.6824, P<0.05), but not with CLZ%dose. The ratios of caffeine metabolism in serum were also correlated with desmethylclozapine AUC0→24(n=9, r=0.7525, P<0.05) and with reciprocals of clozapine AUC0→24(n=9, r=0.8098, P<0.01), respectively. The ratios of caffeine metabolism in urine, (paraxanthine + 1,7-dimethyluric acid)/caffeine, were correlated with desmethylclozapine AUC0→24 (n=9, r=0.8480, P<0.01) and with reciprocals of clozapine AUC0→24(n=9, r=0.6982, P<0.05), respectively. It is concluded that CYP1A2 is involved in demethylation of clozapine in vivo. Close monitoring of clozapine plasma concentration is recommended in patients treated at same time with other drugs affecting CYP1A2.

关 键 词：氯氮平 细胞色素 咖啡因 DCLZ CYP1A2 

分 类 号：R971.43[医药卫生—药品] R969.1[医药卫生—药学]