title: The Use of Transporter Probe Drug Cocktails for the Assessment of Transporter-Based Drug-Drug Interactions in a Clinical Setting-Proposal of a Four Component Transporter Cocktail.
abstract: Probe drug cocktails are used clinically to assess the potential for drug-drug interactions (DDIs), and in particular, DDIs resulting from coadministration of substrates and inhibitors of cytochrome P450 enzymes. However, a probe drug cocktail has not been identified to assess DDIs involving inhibition of drug transporters. We propose a cocktail consisting of the following substrates to explore the potential for DDIs caused by inhibition of key transporters: digoxin (P-glycoprotein, P-gp), rosuvastatin (breast cancer resistance protein, BCRP; organic anion transporting polypeptides, OATP), metformin (organic cation transporter, OCT; multidrug and toxin extrusion transporters, MATE), and furosemide (organic anion transporter, OAT). Furosemide was evaluated in vitro, and is a substrate of OAT1 and OAT3, with Km values of 38.9 and 21.5 μM, respectively. Furosemide was also identified as a substrate of BCRP, OATP1B1, and OATP1B3. Furosemide inhibited BCRP (50% inhibition of drug transport: 170 μM), but did not inhibit OATP1B1, OATP1B3, OCT2, MATE1, and MATE2-K at concentrations below 300 μM, and P-gp at concentrations below 2000 μM. Conservative approaches for the estimation of the likelihood of in vivo DDIs indicate a remote chance of in vivo transporter inhibition by these probe drugs when administered at low single oral doses. This four component probe drug cocktail is therefore proposed for clinical evaluation.
authors.affiliation: Department of Drug Metabolism and Pharmacokinetics, Boehringer Ingelheim Pharma GmbH and Co. KG, Biberach, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Ebner
authors.affiliation: Pharmacokinetics and Non-Clinical Safety Department, Kobe Pharma Research Institute, Nippon Boehringer Ingelheim Company, Ltd., Kobe, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Ishiguro
authors.affiliation: Drug Metabolism and Pharmacokinetics, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut.
authors.forename: Mitchell E
authors.initials: ME
authors.lastname: Taub
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D001692:Biological Transport / Q000502:physiology; D018938:Caco-2 Cells; D002460:Cell Line; D045744:Cell Line, Tumor; D004077:Digoxin / Q000378:metabolism*; D004347:Drug Interactions / Q000502:physiology; D005665:Furosemide / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D008687:Metformin / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000378:metabolism; D027361:Organic Anion Transporters / Q000378:metabolism*; D027701:Organic Cation Transport Proteins / Q000378:metabolism*; D000068718:Rosuvastatin Calcium / Q000378:metabolism*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters; D009363:Neoplasm Proteins; D027361:Organic Anion Transporters; D027701:Organic Cation Transport Proteins; D004077:Digoxin; D005665:Furosemide; D000068718:Rosuvastatin Calcium; D008687:Metformin
keywords: ABC transporters; P-glycoprotein; drug interaction; efflux pumps; inhibition; kinetics; organic anion transporters; organic anion-transporting polypeptide transporters; organic cation transporters