title: Sertraline and its metabolite desmethylsertraline, but not bupropion or its three major metabolites, have high affinity for P-glycoprotein.
abstract: 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, desmethylsertraline, bupropion, and the major metabolites of bupropion, threo-amino alcohol (TB), erythro-amino alcohol (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) 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.
authors.affiliation: Laboratory of Drug Disposition and Pharmacogenetics, Department of Psychiatry and Behavioral Sciencesk, Medical University of South Carolina, Charleston, SC 29425, USA. junsheng.wang@bms.com
authors.forename: Jun-Sheng
authors.initials: JS
authors.lastname: Wang
authors.forename: Hao-Jie
authors.initials: HJ
authors.lastname: Zhu
authors.forename: Bryan Bradford
authors.initials: BB
authors.lastname: Gibson
authors.forename: John Seth
authors.initials: JS
authors.lastname: Markowitz
authors.forename: Jennifer Lyn
authors.initials: JL
authors.lastname: Donovan
authors.forename: Carl Lindsay
authors.initials: CL
authors.lastname: DeVane
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000251:Adenosine Triphosphatases / Q000378:metabolism; D000465:Algorithms; D000928:Antidepressive Agents / Q000378:metabolism*; D018687:Antidepressive Agents, Second-Generation / Q000378:metabolism*; D001812:Blood-Brain Barrier / Q000378:metabolism; D016642:Bupropion / Q000378:metabolism*; D003627:Data Interpretation, Statistical; D006801:Humans; D066298:In Vitro Techniques; D011485:Protein Binding; D020280:Sertraline / Q000031:analogs & derivatives* / Q000378:metabolism
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000928:Antidepressive Agents; D018687:Antidepressive Agents, Second-Generation; D016642:Bupropion; C065162:desmethylsertraline; D000251:Adenosine Triphosphatases; D020280:Sertraline