title: Mechanism of an unusual, but clinically significant, digoxin-bupropion drug interaction.
abstract: An unusual, but clinically significant, digoxin (DIG)-bupropion (BUP) drug interaction (DDI), in which BUP increased DIG renal clearance by 80% is reported. To investigate the mechanism(s) of this unusual DDI, first the effect of BUP, its circulating metabolites or their combination on [(3) H]-DIG transport by cells expressing human P-gp or human OATP4C1 was determined. Second, the study asked whether this DDI could be replicated in the rat so that it could be used to conduct mechanistic studies. Then, the effect of BUP and its rat metabolites on [(3) H]-DIG transport were tested by cells expressing rat Oatp4c1. Bupropion and its metabolites had no effect on human P-gp mediated transepithelial transport of [(3) H]-DIG. Bupropion and hydroxybupropion (HBUP) significantly stimulated H-OATP4C1 mediated transport of [(3) H]-DIG. In addition, BUP cocktail (BUP plus its metabolites) significantly increased the H-OATP4C1 mediated transport of [(3) H]-DIG, and partially reversed the inhibition by 100 µm DIG. However, erythro-hydrobupropion (EBUP) and threo-hydrobupropion (TBUP) did not affect the [(3) H]-DIG uptake by H-OATP4C1 cells. Bupropion administration significantly increased digoxin renal clearance in rats. Surprisingly, bupropion significantly inhibited r-Oatp4c1 mediated transport of [(3) H]-DIG at clinically relevant unbound plasma concentrations of BUP or those observed in the rat study, while HBUP or TBUP did not. These data support our hypothesis that at clinically relevant plasma concentrations, bupropion and its metabolites activate H-OATP4C1 mediated DIG tubular secretion, and could possibly explain the increase in digoxin renal clearance produced by bupropion. While bupropion increased digoxin renal clearance in the rat, it appeared to do so by inhibiting r-Oatp4c1-mediated digoxin renal reabsorption.
authors.affiliation: Department of Pharmaceutics, University of Washington, Seattle, Washington, 98195, USA; Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, Jiangsu, 210009, P.R. China.
authors.forename: Jiake
authors.initials: J
authors.lastname: He
authors.forename: Yang
authors.initials: Y
authors.lastname: Yu
authors.forename: Bhagwat
authors.initials: B
authors.lastname: Prasad
authors.forename: Xijing
authors.initials: X
authors.lastname: Chen
authors.forename: Jashvant D
authors.initials: JD
authors.lastname: Unadkat
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000818:Animals; D001692:Biological Transport; D016642:Bupropion / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000494:pharmacology*; D002316:Cardiotonic Agents / Q000493:pharmacokinetics; D004077:Digoxin / Q000493:pharmacokinetics*; D004285:Dogs; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D004347:Drug Interactions; D005260:Female; D006801:Humans; D061985:Madin Darby Canine Kidney Cells; D027361:Organic Anion Transporters / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013045:Species Specificity
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002316:Cardiotonic Agents; D018765:Dopamine Uptake Inhibitors; D027361:Organic Anion Transporters; C484530:SLCO4C1 protein, human; C496216:hydrobupropion; C580748:hydroxybupropion; C484531:organic anion transporting polypeptide 4C1, rat; D016642:Bupropion; D004077:Digoxin
keywords: H-OATP4C1/r-Oatp4c1; P-gp; bupropion; digoxin; drug-drug interaction