title: Inhibitory Potential of Antifungal Drugs on ATP-Binding Cassette Transporters P-Glycoprotein, MRP1 to MRP5, BCRP, and BSEP.
abstract: Inhibition of ABC transporters is a common mechanism underlying drug-drug interactions (DDIs). We determined the inhibitory potential of antifungal drugs currently used for invasive fungal infections on ABC transporters P-glycoprotein (P-gp), MRP1 to MRP5, BCRP, and BSEP in vitro Membrane vesicles isolated from transporter-overexpressing HEK 293 cells were used to investigate the inhibitory potential of antifungal drugs (250 μM) on transport of model substrates. Concentration-inhibition curves were determined if transport inhibition was >60%. Fifty percent inhibitory concentrations (IC50s) for P-gp and BCRP were both 2 μM for itraconazole, 5 and 12 μM for hydroxyitraconazole, 3 and 6 μM for posaconazole, and 3 and 11 μM for isavuconazole, respectively. BSEP was strongly inhibited by itraconazole and hydroxyitraconazole (3 and 17 μM, respectively). Fluconazole and voriconazole did not inhibit any transport for >60%. Micafungin uniquely inhibited all transporters, with strong inhibition of MRP4 (4 μM). Anidulafungin and caspofungin showed strong inhibition of BCRP (7 and 6 μM, respectively). Amphotericin B only weakly inhibited BCRP-mediated transport (127 μM). Despite their wide range of DDIs, azole antifungals exhibit selective inhibition on efflux transporters. Although echinocandins display low potential for clinically relevant DDIs, they demonstrate potent in vitro inhibitory activity. This suggests that inhibition of ABC transporters plays a crucial role in the inexplicable (non-cytochrome P450-mediated) DDIs with antifungal drugs.
authors.affiliation: Radboud University Medical Center, Department of Pharmacy, Nijmegen, The Netherlands Radboud Institute for Health Sciences, Nijmegen, The Netherlands.
authors.forename: Vincent J C
authors.initials: VJ
authors.lastname: Lempers
authors.affiliation: Radboud University Medical Center, Department of Pharmacology and Toxicology, Nijmegen, The Netherlands Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands.
authors.forename: Jeroen J M W
authors.initials: JJ
authors.lastname: van den Heuvel
authors.affiliation: Radboud University Medical Center, Department of Pharmacology and Toxicology, Nijmegen, The Netherlands Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands.
authors.forename: Frans G M
authors.initials: FG
authors.lastname: Russel
authors.affiliation: Radboud University Medical Center, Department of Pharmacy, Nijmegen, The Netherlands Radboud Institute for Health Sciences, Nijmegen, The Netherlands.
authors.forename: Rob E
authors.initials: RE
authors.lastname: Aarnoutse
authors.affiliation: Radboud University Medical Center, Department of Pharmacy, Nijmegen, The Netherlands Radboud Institute for Health Sciences, Nijmegen, The Netherlands.
authors.forename: David M
authors.initials: DM
authors.lastname: Burger
authors.affiliation: Radboud University Medical Center, Department of Pharmacy, Nijmegen, The Netherlands Radboud Institute for Health Sciences, Nijmegen, The Netherlands roger.Bruggemann@radboudumc.nl.
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Brüggemann
authors.affiliation: Radboud University Medical Center, Department of Pharmacology and Toxicology, Nijmegen, The Netherlands Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands.
authors.forename: Jan B
authors.initials: JB
authors.lastname: Koenderink
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000378:metabolism*; D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2 / Q000378:metabolism*; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000666:Amphotericin B / Q000494:pharmacology; D000935:Antifungal Agents / Q000494:pharmacology*; D001692:Biological Transport / Q000187:drug effects; D054714:Echinocandins / Q000494:pharmacology; D015725:Fluconazole / Q000494:pharmacology; D057809:HEK293 Cells; D006801:Humans; D017964:Itraconazole / Q000031:analogs & derivatives / Q000494:pharmacology; D055666:Lipopeptides / Q000494:pharmacology; D000077551:Micafungin; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000378:metabolism*; D014230:Triazoles / Q000494:pharmacology; D065819:Voriconazole / Q000494:pharmacology
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000666:Amphotericin B; D000935:Antifungal Agents; D054714:Echinocandins; D015725:Fluconazole; D017964:Itraconazole; D055666:Lipopeptides; D000077551:Micafungin; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009363:Neoplasm Proteins; D014230:Triazoles; D065819:Voriconazole; C093491:ABCB11 protein, human; C120809:ABCC5 protein, human; C116614:ABCG2 protein, human; C084794:hydroxyitraconazole; C101425:posaconazole; C421109:multidrug resistance-associated protein 1