氟西汀和圣约翰草提取物对环孢素体外经CYP3A4代谢的影响  

Effects of fluoxetine,norfluoxetine and extracts of Saint John's Wort on metabolism of cyclosporine in vitro via recombinant human CYP3A4

作　　者：刘治军[1] 刘宁[2] 孙春华[1] 迟家敏[1] 

机构地区：[1]卫生部北京医院,北京100730 [2]北京大学药学院药事管理与临床药学系,北京100083

出　　处：《中国新药杂志》2009年第2期155-158,182,共5页Chinese Journal of New Drugs

摘　　要：目的:体外考察抗抑郁药氟西汀、去甲氟西汀和圣约翰草提取物对免疫抑制剂环孢素在细胞色素P450酶介导的代谢的影响,为临床器官移植术后合理选择抗抑郁药提供参考。方法:建立以重组人CYP3A4代谢酶的体外反应体系,将氟西汀、去甲氟西汀和圣约翰草提取物分别与环孢素共孵育,用高效液相色谱-紫外检测器(HPLC-UV)法测定孵育液中环孢素浓度。结果:系列浓度的氟西汀、去甲氟西汀和圣约翰草提取物与2 nmol.mL-1环孢素共孵育后,计算求得IC50值分别为609,205和224μmol.L-1,Ki值分别为71.45,61.15和80.13μmol.L-1;阳性对照药红霉素能显著抑制环孢素的体外代谢,其IC50=120μmol.L-1,Ki值为47.32μmol.L-1。结论:氟西汀体外对CYP3A4有轻微的抑制作用,其体内代谢物去甲氟西汀能显著抑制环孢素的代谢,可为氟西汀和环孢素是否产生临床意义的相互作用提供参考;圣约翰草提取物体外亦能显著抑制环孢素经CYP3A4的代谢。Objective：We determined the in vitro effects of three antidepressants, fluoxetine, norfluoxetine and extracts of Saint John＇s Wort, on cyclosporine A （CsA） metabolism via recombinant human CYP3A4, for clinician＇s rational choice of antidepressants in transplantation patients using immunodepressants. Methods ： To test drug-drug interaction in vitro, a recombinant human CYP3A4 was adopted to simulate in vivo hepatic microsome reaction system. The effects of three antidepressant drugs on CsA metabolism were evaluated by measuring the CsA concentration changes using high performance liquid chromatography with a UV detector （HPLC-UV）. Results： After CsA （2 nmol·mL^-1 ） were incubated with series concentrations of fluoxetine, norfluoxetine and extracts of Saint John＇s Wort, its values of IC50 were 609, 205 and 224umol·mL^-1 , and the values of Ki were 71.45, 61.15 and 80.13 umol·mL^-1, respectively. The positive control erythromycin significantly inhibited CsA metabolism, and the IC50 and K8 values of CsA were 120umol·mL^-1 and 47.32umol·mL^-1. Conclusion： Fluoxetin mildly inhibits CsA metabolism while its metabolite norfluoxetine strongly inhibits CsA metabolism via CYP3A4, indicating the clinically significant in vivo interaction between fluoxetine and CsA. The extract of Saint John＇s Wort also significantly inhibits CsA metabolism via CYP3A4 in vitro.

关 键 词：环孢素 氟西汀 去甲氟西汀 圣约翰草提取物 药物相互作用 CYP3A4 

分 类 号：R971.43[医药卫生—药品]