氟伏沙明抑制体内氯氮平代谢的药代动力学研究  

INHIBITION OF CLOZAPINE METABOLISM BY FLUVOXAMINE: A PHARMACOKINETIC STUDY IN MAN

作　　者：王传跃[1,2,3] 周宏灏[1,2,3] 杨德森[1,2,3] 陈远光 赵靖平[1,2,3] 许振华 朱荣华[1,2,3] 

机构地区：[1]湖南医科大学精神卫生研究所 [2]湖南医科大学遗传药理学研究所 [3]首都医科大学附属北京安定医院

出　　处：《中国临床药理学杂志》1999年第4期270-272,276,共4页The Chinese Journal of Clinical Pharmacology

摘　　要：通过检测氯氮平和去甲氯氮平血清浓度，探讨细胞色素Ｐ４５０１Ａ２酶（ＣＹＰ１Ａ２）抑制剂氟伏沙明对体内氯氮平代谢及其去甲基代谢产物生成的影响。９例健康男性志愿者，自身前后对照设计，停药间隔４周，口服单剂氯氮平１０ｍｇ；对照组单服氯氮平，实验组是在氟伏沙明连续９ｄ服用过程中的第４ｄ合用单剂氯氮平。合用氟伏沙明后，导致氯氮平的清除相时点平均浓度增高，去甲氯氮平的早期时点平均浓度降低而后期时点平均浓度增高。合用氟伏沙明前后比较，可见氯氮平的消除半衰期Ｔ１／２、０～２４ｈ药时曲线下面积ＡＵＣ０～２４以及系统清除率Ｃｌｓ的差异有显著意义（Ｐ＜０．０１）。研究结果表明，氟伏沙明显著抑制体内氯氮平的代谢，影响其去甲基代谢产物的生成。ＣＹＰ１Ａ２可能是催化体内氯氮平去甲基代谢的主要代谢酶。The aim of the present study was to assess the possible effect of the CYP1A2 inhibitor fluvoxamine on the disposition of clozapine and metabolite N-desmethylclozapine in vivo. Nine male volunteers were enrolled in the study. They were assigned to two sessions with a drug-free interval of at least 4 weeks. All subjects received a single oral dose of clozapine 10 mg. In the control session the drug was taken alone, while in the concomitant fluvoxamine session clozapine was administered on the 4th day of a 9-day treatment with fluvoxamine. After the coadministration with fluvoxamine, mean clozapine concentrations in serum were increased throughout the sampling points of clozapine clearance phase, which accompanied by the decrease of mean desmethylclozapine concentrations in serum during early phase but the increase during later phase. Compared with the control session, concomitant fluvoxamine intake was associated with a prolongation in clozapine T1/2 (from 27.71 to 131.33 hours, P<0.01), with increased clozapine AUC 0～24 (from 267.80 to 373.74 μg·L-1, P<0.01) and with a reduction in clozapine Cls (from 5.86 to 1.28 ml·min-1·kg-1, P<0.01). These results suggest that fluvoxamine markedly inhibit the metabolism of clozapine, and to a certain extent, can affect the formation of desmethylclozapine. CYP1A2 may be one of the major enzymes forming desmethylclozapine in vivo.

关 键 词：氯氮平 氟伏沙明 药代动力学 抑制剂 

分 类 号：R971.4[医药卫生—药品] R969.1[医药卫生—药学]