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Hepatic drug transporters play a pivotal role in the excretion of drugs from the body, in drug-drug interactions, as well as in drug-induced liver toxicity. Hepatocytes cultured in sandwich configuration are an advantageous model to investigate the interactions of drug candidates with apical efflux transporters in a biorelevant manner. However, the commonly used "offline" assays (i.e., that rely on measuring intracellular accumulated amounts after cell lysis) are time- and resource-consuming, and the data output is often highly variable. In the present study, we used confocal microscopy to investigate the inhibitory effect of all marketed HIV protease inhibitors (10 μ M) on the apical efflux transporter multidrug resistance-associated protein 2 (MRP2; ABCC2) by visualizing the biliary accumulation of the fluorescent substrate 5(6)-carboxy-2',7'-dichlorofluorescein (CDF). This method was applied with sandwich-cultured human and rat hepatocytes. Alterations in the biliary excretion index of CDF were calculated on the basis of quantitative analysis of fluorescence intensities in the confocal images. In human hepatocytes, lopinavir followed by tipranavir, saquinavir, atazanavir, and darunavir were the most potent inhibitors of MRP2-mediated efflux of CDF. In rat hepatocytes, tipranavir inhibited Mrp2-mediated CDF efflux most potently, followed by lopinavir and nelfinavir. In conclusion, a comparison of these findings with previously published data generated in offline transporter inhibition assays indicates that this microscopy-based approach enables investigation of the inhibitory effect of drugs on efflux transporters in a very sensitive but nondestructive manner.

MRP2 Inhibition by HIV Protease Inhibitors in Rat and Human Hepatocytes: A Quantitative Confocal Microscopy Study