title: ITC commentary on the prediction of digoxin clinical drug-drug interactions from in vitro transporter assays.
abstract: The "P-glycoprotein" IC50 working group reported an 18- to 796-fold interlaboratory range in digoxin transport IC50 (inhibitor concentration achieving 50% of maximal inhibition), raising concerns about the predictability of clinical transporter-based drug-drug interactions (DDIs) from in vitro data. This Commentary describes complexities of digoxin transport, which involve both uptake and efflux processes. We caution against attributing digoxin transport IC50 specifically to P-glycoprotein (P-gp) or extending this composite uptake/efflux IC50 variability to individual transporters. Clinical digoxin interaction studies should be interpreted as evaluation of digoxin safety, not P-gp DDIs.
authors.affiliation: QPS DMPK Hepatic Biosciences, Research Triangle Park, North Carolina, USA.
authors.forename: C A
authors.initials: CA
authors.lastname: Lee
authors.affiliation: Drug Metabolism, Pharmacokinetics, and Bioanalysis, AbbVie, North Chicago, Illinois, USA.
authors.forename: J C
authors.initials: JC
authors.lastname: Kalvass
authors.affiliation: Centre for Applied Pharmacokinetic Research, Manchester Pharmacy School, The University of Manchester, Manchester, UK.
authors.forename: A
authors.initials: A
authors.lastname: Galetin
authors.affiliation: Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, Research Triangle Park, North Carolina, USA.
authors.forename: M J
authors.initials: MJ
authors.lastname: Zamek-Gliszczynski
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D001692:Biological Transport; D002317:Cardiovascular Agents / Q000009:adverse effects / Q000378:metabolism* / Q000493:pharmacokinetics; D004077:Digoxin / Q000009:adverse effects / Q000378:metabolism* / Q000493:pharmacokinetics; D004347:Drug Interactions; D006801:Humans; D026901:Membrane Transport Proteins / Q000187:drug effects* / Q000378:metabolism; D008954:Models, Biological; D061214:Patient Safety; D018570:Risk Assessment; D012307:Risk Factors
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002317:Cardiovascular Agents; D026901:Membrane Transport Proteins; D004077:Digoxin