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Antimicrobial Agents and Chemotherapy, January 2002, p. 160-165, Vol. 46, No. 1
0066-4804/01/$04.00+0     DOI: 10.1128/AAC.46.1.160-165.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Interaction of Common Azole Antifungals with P Glycoprotein

Er-jia Wang, Karen Lew, Christopher N. Casciano, Robert P. Clement, and William W. Johnson*

Drug Metabolism and Pharmacokinetics, Schering-Plough Research Institute, Lafayette, New Jersey 07848

Received 13 June 2001/ Returned for modification 8 August 2001/ Accepted 1 October 2001

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 (IC50s) of ~2 and ~6 µM, respectively. Cyclosporin A was inhibitory with an IC50 of 1.4 µM 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 Km values were congruent with the IC50s. 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.

* Corresponding author. Mailing address: Schering-Plough Research Institute, 144 Route 94, P.O. Box 32, Lafayette, NJ 07848. Phone: (973) 940-4336. Fax: (973) 940-4211. E-mail: William.w.johnson{at}spcorp.com.

Antimicrobial Agents and Chemotherapy, January 2002, p. 160-165, Vol. 46, No. 1
0066-4804/01/$04.00+0     DOI: 10.1128/AAC.46.1.160-165.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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