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

Abstract

dInhibition 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 M) on transport of model substrates. Concentration-inhibition curves were determined if transport inhibition was >60%. Fifty percent inhibitory concentrations (IC 50 s) for P-gp and BCRP were both 2 M for itraconazole, 5 and 12 M for hydroxyitraconazole, 3 and 6 M for posaconazole, and 3 and 11 M for isavuconazole, respectively. BSEP was strongly inhibited by itraconazole and hydroxyitraconazole (3 and 17 M, respectively). Fluconazole and voriconazole did not inhibit any transport for >60%. Micafungin uniquely inhibited all transporters, with strong inhibition of MRP4 (4 M). Anidulafungin and caspofungin showed strong inhibition of BCRP (7 and 6 M, respectively). Amphotericin B only weakly inhibited BCRP-mediated transport (127 M). 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. Invasive fungal infections are a leading cause of infection-related mortality in immunocompromised individuals and patients with serious underlying conditions. Although prophylactic or therapeutic use of azole antifungal drugs has substantially improved treatment outcome, these drugs display a significant potential for clinically relevant drug-drug interactions (DDIs) (1, 2). As a result, the pharmacokinetics (PK) of both drugs may alter, resulting in either increased plasma concentrations with subsequent risk of adverse events or subtherapeutic plasma concentrations potentially leading to therapeutic failure.With regard to phase I and II enzymes, the pharmacokinetic profiles of antifungal drugs have been quite well characterized (2, 3). Yet it also appears that both uptake and efflux transporters are considered a major intervenient in drug PK, and inhibition of such transporters is an important mechanism underlying DDIs (4, 5).Transporters of the ATP-binding cassette (ABC) transporter protein family are involved in unidirectional, cellular efflux of drugs (6). They are multidomain, integral membrane proteins which all exhibit the capacity to actively transport physiological substrates (e.g., peptides, lipids, and inorganic ions) across extraand intracellular membranes at the expense of ATP hydrolysis. Expression of these transporters in the cellular membranes of the gastrointestinal tract, blood-brain barrier, liver, and kidneys suggests that they also hold a key position in the cellu...

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