细胞色素P4502B6（CYP2B6）和人肝微粒体对安非他酮的立体选择性代谢。
Stereoselective metabolism of bupropion by cytochrome P4502B6 (CYP2B6) and human liver microsomes.
作者信息
Coles Rebecka, Kharasch Evan D
机构信息
Division of Clinical and Translational Research, Department of Anesthesiology, Washington University, St. Louis, Missouri 63110-1093, USA.
出版信息
Pharm Res. 2008 Jun;25(6):1405-11. doi: 10.1007/s11095-008-9535-1.
PURPOSE
Hydroxylation of the antidepressant and smoking deterrent drug bupropion is a clinically important bioactivation and elimination pathway. Bupropion hydroxylation is catalyzed selectively by cytochrome P4502B6 (CYP2B6). CYP2B6-catalyzed bupropion hydroxylation has been used as an in vitro and in vivo phenotypic probe for CYP2B6 activity and CYP2B6 drug interactions. Bupropion is chiral, used clinically as a racemate, and disposition is stereoselective. Nevertheless, it is unknown whether CYP2B6-catalyzed bupropion hydroxylation is stereoselective.
METHODS
Hydroxylation of racemic bupropion by recombinant CYP2B6 and human liver microsomes was evaluated using a stereoselective assay.
RESULTS
At therapeutic concentrations, hydroxylation of (S)-bupropion was threefold and 1.5-greater than (R)-bupropion, respectively, by recombinant CYP2B6 and human liver microsomes. In vitro intrinsic clearances were likewise different for bupropion enantiomers.
CONCLUSIONS
Stereoselective bupropion hydroxylation may have implications for the therapeutic efficacy of bupropion as an antidepressant or smoking cessation therapy, and for the use of bupropion as an in vivo phenotypic probe for CYP2B6 activity.
目的
抗抑郁及戒烟药物安非他酮的羟基化是一条具有临床重要性的生物活化及消除途径。安非他酮羟基化由细胞色素P4502B6（CYP2B6）选择性催化。CYP2B6催化的安非他酮羟基化已被用作CYP2B6活性及CYP2B6药物相互作用的体外及体内表型探针。安非他酮具有手性，临床使用外消旋体，其处置具有立体选择性。然而，CYP2B6催化的安非他酮羟基化是否具有立体选择性尚不清楚。
方法
使用立体选择性分析评估重组CYP2B6和人肝微粒体对外消旋安非他酮的羟基化作用。
结果
在治疗浓度下，重组CYP2B6和人肝微粒体对（S）-安非他酮的羟基化作用分别比对（R）-安非他酮高3倍和1.5倍。安非他酮对映体的体外内在清除率同样存在差异。
结论
安非他酮的立体选择性羟基化可能对其作为抗抑郁药或戒烟疗法的治疗效果以及作为CYP2B6活性的体内表型探针的应用产生影响。
Zotero 插件