Fax +41 61 306 12 34 E-Mail karger@karger.ch www.karger.com Original Paper Med Princ Pract 2008;17:117–121 DOI: 10.1159/000112964 Effect of Chemosensitizers on Minimum Inhibitory Concentrations of Fluconazole in Candida albicans Nailya R. Bulatova a Rula M. Darwish b Departments of a Biopharmaceutics and Clinical Pharmacy and b Pharmaceutical Sciences, Faculty of Pharmacy, University of Jordan, Amman, Jordan brozil, 0.83 g/ml by quinine, and 0.76 g/ml by chlorprom- azine in the reference strain, with MIC reduction to 0.08 g/ml by all three chemosensitizers in the clinical isolate. Some double combinations reduced the MIC of fluconazole to 10- to 100-fold, even when the chemosensitizers were not effective alone. Conclusion: The most effective double com- binations were those of chlorpromazine with either reser- pine or nicardipine. Copyright © 2008 S. Karger AG, Basel Introduction The wide use of fluconazole for the treatment of Can- dida albicans infections and other mycoses is currently hindered by the appearance of resistant strains [1–3]. The most prevalent resistance pattern appears to be decreased drug accumulation due to increased expression of efflux pumps on the plasma membrane of fungal cells, either the major facilitators such as multidrug resistance (MDR) [4, 5] and FLU [6, 7] or the ABC transporters CDR1 [5, 8] and CDR2 [9, 10]. It has been demonstrated that drug-extruding efflux pumps in C. albicans possess sequences with a high de- gree of homology to the product of human MDR-1 gene that confers MDR to anticancer drugs [11] . Examples of MDR-reversing agents (chemosensitizers) include calci- Key Words Candida albicans  Fluconazole  Chemosensitizers Abstract Objective: To evaluate the effect of chemosensitizers on the in vitro activity of fluconazole against Candida albicans strains. Materials and Methods: Using Clinical Laboratory Standard Institute method, antifungal activity of fluconazole was determined alone and in combination with 16 chemo- sensitizers that included verapamil, reserpine, quinine, quinidine, gemfibrozil, lansoprazole, tamoxifen, diltiazem, desipramine, nicardipine, cyclosporine, chlorpromazine, prochlorperazine, promethazine, thioridazine, and trifluo- perazine. Further studies were done using double combina- tions of selected chemosensitizers with fluconazole (28 combinations). For testing combinations, half of the mini- mum inhibitory concentration (MIC) of each agent was se- lected in order to avoid the effect of the drug alone. One reference strain (ATCC90028) and one clinical isolate of C. al- bicans were used for testing the in vitro activity. Broth dilu- tion method was used to determine the MICs of fluconazole and chemosensitizers. Results: Of the 16 chemosensitizers tested, 3 exhibited in vitro activity by increasing fluconazole susceptibility to 7-fold. The MICs of the reference strain and clinical isolate for fluconazole were 5.5 and 0.55 g/ml, re- spectively, and these were reduced to 0.76 g/ml by gemfi- Received: February 6, 2007 Revised: August 13, 2007 Dr. Nailya Bulatova Department of Biopharmaceutics and Clinical Pharmacy Faculty of Pharmacy, University of Jordan PO Box, Amman 11942 (Jordan) Tel. +962 535 5000, ext. 2507 or 2478, Fax +962 6533 9649, E-Mail nyounes@ju.edu.jo © 2008 S. Karger AG, Basel 1011–7571/08/0172–0117$24.50/0 Accessible online at: www.karger.com/mpp