Inhibitory Potential of Antifungal Drugs on ATP-Binding Cassette Transporters P-Glycoprotein, MRP1 to MRP5, BCRP, and BSEP.

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Lempers VJ, van den Heuvel JJ, Russel FG, Aarnoutse RE, Burger DM, Bruggemann RJ, Koenderink JB

Inhibitory Potential of Antifungal Drugs on ATP-Binding Cassette Transporters P-Glycoprotein, MRP1 to MRP5, BCRP, and BSEP.

Antimicrob Agents Chemother. 2016 May 23;60(6):3372-9. doi: 10.1128/AAC.02931-15. Print 2016 Jun.

PubMed ID

27001813 [ View in PubMed

]

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 muM) 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 muM for itraconazole, 5 and 12 muM for hydroxyitraconazole, 3 and 6 muM for posaconazole, and 3 and 11 muM for isavuconazole, respectively. BSEP was strongly inhibited by itraconazole and hydroxyitraconazole (3 and 17 muM, respectively). Fluconazole and voriconazole did not inhibit any transport for >60%. Micafungin uniquely inhibited all transporters, with strong inhibition of MRP4 (4 muM). Anidulafungin and caspofungin showed strong inhibition of BCRP (7 and 6 muM, respectively). Amphotericin B only weakly inhibited BCRP-mediated transport (127 muM). 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.

DrugBank Data that Cites this Article

Drug Transporters

Drug	Transporter	Kind	Organism	Pharmacological Action	Actions
Caspofungin	P-glycoprotein 1	Protein	Humans	Unknown	Inhibitor	Details

Drug Interactions

Drugs	Interaction
Integrate drug-drug interactions in your software
Riociguat Ritonavir	The serum concentration of Riociguat can be increased when it is combined with Ritonavir.
Riociguat Amiodarone	The serum concentration of Riociguat can be increased when it is combined with Amiodarone.
Riociguat Midostaurin	The serum concentration of Riociguat can be increased when it is combined with Midostaurin.
Riociguat Voriconazole	The serum concentration of Riociguat can be increased when it is combined with Voriconazole.
Riociguat Efavirenz	The serum concentration of Riociguat can be increased when it is combined with Efavirenz.