P-glycoprotein inhibition by the agricultural pesticide propiconazole and its hydroxylated metabolites: Implications for pesticide–drug interactions

摘要: The human efflux transporter P-glycoprotein (P-gp, MDR1) functions as an important cellular defense system against a variety of xenobiotics; however, little information exists on whether environmental chemicals interact with P-gp. Conazoles provide unique challenge to exposure assessment because their use both pesticides and drugs. Propiconazole is agricultural pesticide undergoing evaluation by the U.S. Environmental Protection Agency's Endocrine Disruptor Screening Program. In this study, P-gp interaction propiconazole its hydroxylated metabolites were evaluated using MDR1-expressing membrane vesicles NIH-3T3/MDR1 cells. Membrane vesicle assays demonstrated (IC50,122.9μM) (IC50s, 350.8μM, 366.4μM, 456.3μM) inhibited probe substrate, demonstrating strongest interaction. mediated transport in MDR1-expressed was not detected indicating interacts inhibitor rather than substrate. cells, (1 10μM) led decreased resistance (chemosensitization) paclitaxel, chemotherapeutic drug known MDR1 Collectively, these results have pharmacokinetic risk implications may influence toxicity potential for pesticide-drug interactions.