Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
2487624 | Journal of Pharmaceutical Sciences | 2007 | 10 Pages |
Abstract
Breast cancer resistance protein (BCRP) is an efflux transporter that plays an important role in drug disposition. The goal of this study was to investigate the interactions of azole antifungal agents, ketoconazole, itraconazole, fluconazole, and voriconazole, with BCRP. First, the effect of the azoles on BCRP efflux activity in BCRPâoverexpressing HEK cells was determined by measuring intracellular pheophorbide A (PhA) fluorescence using flow cytometry. We found that keotoconazole and itraconazole significantly inhibited BCRPâmediated efflux of PhA at low µM concentrations. However, fluconazole only mildly inhibited and voriconazole did not inhibit BCRP efflux activity at concentrations up to 100 µM. The IC50 value of ketoconazole for inhibition of BCRPâmediated PhA efflux was 15.3 ± 6.5 µM. Ketoconazole and itraconazole also effectively reversed BCRPâmediated resistance of HEK cells to topotecan. When direct efflux of [3H]ketoconazole was measured in BCRPâoverexpressing HEK cells, we found that [3H]ketoconazole was not transported by BCRP. Consistent with this finding, BCRP did not confer resistance to ketoconazole and itraconazole in HEK cells. Taken together, ketoconazole and itraconazole are BCRP inhibitors, but fluconazole and voriconazole are not. These results suggest that BCRP could play a significant role in the pharmacokinetic interactions of ketoconazole or itraconazole with BCRP substrate drugs. © 2007 WileyâLiss, Inc. and the American Pharmacists Association J Pharm Sci 96: 3226-3235, 2007
Keywords
Related Topics
Health Sciences
Pharmacology, Toxicology and Pharmaceutical Science
Drug Discovery
Authors
Anshul Gupta, Jashvant D. Unadkat, Qingcheng Mao,