Sertraline and its metabolite desmethylsertraline, but not bupropion or its three major metabolites, have high affinity for P-glycoprotein
Sertraline and its metabolite desmethylsertraline, but not bupropion or its three major metabolites, have high affinity for P-glycoprotein
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DOI：
10.1248/bpb.31.231
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发表时间：
2008-02-01
影响因子：
2
通讯作者：
DeVane, Carl Lindsay
中科院分区：
文献类型：
--
作者：
Wang, Jun-Sheng;Zhu, Hao-Jie;DeVane, Carl Lindsay
ATP结合盒（ABC）转运蛋白亚家族B1系（ABCB 1）转运蛋白P-糖蛋白（P-gp）在血脑屏障中发挥重要作用，限制广谱底物进入中枢神经系统。在本研究中，通过测量表达的人P-gp膜中无机Pi的浓度，在表达的人P-gp膜中使用ATP酶测定法研究了P-gp对舍曲林、去甲基舍曲林、安非他酮以及安非他酮的主要代谢产物苏型氨基醇（TB）、赤型氨基醇（EB）和羟基代谢产物（HB）的转运活性。包括维拉帕米作为阳性对照。动力学数据采用Michaelis-Menten方程表征。舍曲林和去甲基舍曲林对P-gp有较高的亲和力。舍曲林（1.6 min（-1）x 10（-3））和去甲基舍曲林（1.4 min（-1）x 10（-3））的V-max/K-m值与维拉帕米（1.7 min（-1）x 10（-3））相当。安非他酮及其三种代谢产物对P-gp的亲和力非常弱，V-max/K-m值低于0.01 min（-1）x 10（-3）。本研究的结果表明，舍曲林和去甲基舍曲林对P-gp具有高亲和力，而安非他酮及其三种主要代谢产物TB、EB和HB对P-gp的亲和力很弱。这些发现可能有助于解释观察到的抗抑郁药之间的药物相互作用。
The ATP-binding cassette (ABC) transporter protein subfamily B1 line (ABCB1) transporter P-glycoprotein (P-gp) plays an important role in the blood-brain barrier limiting a broad spectrum of substrates from entering the central nervous system. In the present study, the transport activity of P-gp for sertraline, desmethylsertralin, bupropion, and the major metabolites of bupropion, threo-amino alcohol (TB), erythro-amino alchhol (EB), and hydroxy metabolite (HB) was studied using an ATPase assay in expressed human P-gp membranes by measuring concentrations of inorganic Pi in expressed human P-gp membranes. Verapamil was included as a positive control. The Michaelis-Menten equation was used for characterizing the kinetic data. Sertraline and desmethylsertraline showed high affinity for P-gp. The V-max/K-m values of sertraline (1.6 min(-1) x 10(-3)) and desmethylsertraline (1.4 min(-1) x 10(-3)) were comparable with that of verapamil (1.7 min(-1) x 10(-3)). Bupropion and its three metabolites showed very weak affinity for P-gp, with V-max/K-m values lower than 0.01 min(-1) x 10(-3). The results of the present study indicate that sertraline and desmethylsertraline have high affinity for P-gp, whereas bupropion and its three major metabolites TB, EB, and HB have very weak affinity for P-gp. These findings may help to explain observed drug-drug interactions among antidepressants.