title: Evaluation of in vivo P-glycoprotein phenotyping probes: a need for validation.
abstract: Drug transporters are involved in clinically relevant drug-drug interactions. P-glycoprotein (P-gp) is an efflux transporter that displays genetic polymorphism. Phenotyping permits evaluation of real-time, in vivo P-gp activity and P-gp-mediated drug-drug interactions. Digoxin, fexofenadine, talinolol and quinidine are commonly used probe drugs for P-gp phenotyping. Although current regulatory guidance documents highlight methodologies for evaluating transporter-based drug-drug interactions, whether current probe drugs are suitable for phenotyping has not been established, and validation criteria are lacking. This review proposes validation criteria and evaluates P-gp probes to determine probe suitability. Based on these criteria, digoxin, fexofenadine, talinolol and quinidine have limitations to their use and are not recommended for P-gp phenotyping.
authors.affiliation: University of California, San Diego, La Jolla, 92093, USA. joema@ucsd.edu
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Ma
authors.forename: Shirley M
authors.initials: SM
authors.lastname: Tsunoda
authors.forename: Joseph S
authors.initials: JS
authors.lastname: Bertino
authors.forename: Meghana
authors.initials: M
authors.lastname: Trivedi
authors.forename: Keola K
authors.initials: KK
authors.lastname: Beale
authors.forename: Anne N
authors.initials: AN
authors.lastname: Nafziger
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics* / Q000378:metabolism*; D004077:Digoxin / Q000493:pharmacokinetics; D004347:Drug Interactions / Q000235:genetics*; D005838:Genotype; D006801:Humans; D010597:Pharmacogenetics; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D055553:Prescription Drugs / Q000493:pharmacokinetics*; D011412:Propanolamines / Q000493:pharmacokinetics; D011802:Quinidine / Q000493:pharmacokinetics; D015203:Reproducibility of Results; D016593:Terfenadine / Q000031:analogs & derivatives / Q000493:pharmacokinetics
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D055553:Prescription Drugs; D011412:Propanolamines; C011550:talinolol; D004077:Digoxin; D016593:Terfenadine; C093230:fexofenadine; D011802:Quinidine