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标题：Sertraline and Its Metabolite Desmethylsertraline, but not Bupropion or Its Three Major Metabolites, Have High Affinity for P-Glycoprotein
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作者：Jun-Sheng Wang ; Hao-Jie Zhu ; Bryan Bradford Gibson 等
期刊名称：Biological and Pharmaceutical Bulletin
印刷版ISSN：0918-6158
电子版ISSN：1347-5215
出版年度：2008
卷号：31
期号：2
页码：231-234
DOI：10.1248/bpb.31.231
出版社：The Pharmaceutical Society of Japan
摘要：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 P_i 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⁻¹×10⁻³) and desmethylsertraline (1.4 min⁻¹×10⁻³) were comparable with that of verapamil (1.7 min⁻¹×10⁻³). Bupropion and its three metabolites showed very weak affinity for P-gp, with V _max/ K _m values lower than 0.01 min⁻¹×10⁻³. 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.
关键词：P-glycoprotein;sertraline;desmethylsertraline;bupropion;antidepressant;blood–brain barrier