Interaction of Common Azole Antifungals with P Glycoprotein

Abstract

Both eucaryotic and procaryotic cells are resistant to a large number of antibiotics because of the activities of export transporters. The most studied transporter in the mammalian ATP-binding cassette transporter superfamily, P glycoprotein (P-gp), ejects many structurally unrelated amphiphilic and lipophilic xenobiotics. Observed clinical interactions and some in vitro studies suggest that azole antifungals may interact with P-gp. Such an interaction could both affect the disposition and exposure to azole antifungal therapeutics and partially explain the clinical drug interactions observed with some antifungals. Using a whole-cell assay in which the retention of a marker substrate is evaluated and quantified, we studied the abilities of the most widely prescribed orally administered azole antifungals to inhibit the function of this transporter. In a cell line presenting an overexpressed amount of the human P-gp transporter, itraconazole and ketoconazole inhibited P-gp function with 50% inhibitory concentrations (IC 50 s) of ϳ2 and ϳ6 M, respectively. Cyclosporin A was inhibitory with an IC 50 of 1.4 M in this system. Uniquely, fluconazole had no effect in this assay, a result consistent with known clinical interactions. The effects of these azole antifungals on ATP consumption by P-gp (representing transport activity) were also assessed, and the K m values were congruent with the IC 50 s. Therefore, exposure of tissue to the azole antifungals may be modulated by human P-gp, and the clinical interactions of azole antifungals with other drugs may be due, in part, to inhibition of P-gp transport.

The farnesyl transferase inhibitor, tipifarnib, is a potent inhibitor of the MDR1 gene product, P-glycoprotein, and demonstrates significant cytotoxic synergism against human leukemia cell lines

“…25 Lonafarnib is a structural analog of a calmodulin antagonist, whereas tipifarnib is a heterocyclic imidazolecontaining compound that is similar in structure to the azole antifungals, which are also Pgp inhibitors. 25,26 Therefore, despite possessing both Pgp and FT inhibitory activities, these compounds are unlikely to inhibit Pgp function through interaction at the same drug-binding site.…”

Co-administration of Fluoxetine Alters the Steady State Pharmacokinetics of Fluconazole after Multiple Oral Administration in Dogs

“…Xenobiotics that act as substrates for OATP can also serve as substrates for P-gp; consequently they may represent an important factor in drug interaction [25,26]. Azoles such as fluconazole and others can be both substrate and inhibitor of the P-gp; making the effects of P-gp efflux on azole absorption difficult to predict in individual patients [27,28].…”

Has the era of individualised medicine arrived for antifungals? A review of antifungal pharmacogenomics

“…45 Substrate 166 and inhibitor of P-gp. 160,161,167 Conflicting data as to inhibitory effect on OATP. 168,169 Inhibitor of multidrug resistance protein 3.…”

“…Fluconazole Potent inhibitor of CYP2C9 and CYP2C19, 44,45 and less so for CYP3A4. 160 No inhibition of P-gp [160][161][162] or BCRP. 163 Interaction with ciclosporin via CYP inhibition causes increased ciclosporin levels, especially with oral fluconazole.…”