Inhibition of MRP1/ABCC1, MRP2/ABCC2, and MRP3/ABCC3 by Nucleoside, Nucleotide, and Non-Nucleoside Reverse Transcriptase Inhibitors

Abstract

ABSTRACT:Many drug interactions with drugs used for the therapy of human immunodeficiency virus (HIV) occur at the level of different cytochrome P450 isozymes. Increasing evidence suggests that antiretrovirals may also modify activity and expression of active drug transport systems. Such interactions may alter drug absorption, elimination, and also drug distribution and reach clinical importance if thereby access to the target site is affected. Beyond P-glycoprotein, the family of multidrug resistance-related proteins (MRP/ABCC) substantially contributes to the elimination of numerous drugs and their metabolites. Because the interaction of MRPs with non-HIV protease inhibitor antiretrovirals has not been studied thoroughly, we investigated whether important non-nucleoside reverse transcriptase inhibitors (NNRTI) (delavirdine, efavirenz, and nevirapine), nucleoside reverse transcriptase inhibitors (NRTI) (abacavir, emtricitabine, and lamivudine), and tenofovir as a nonnucleotide reverse transcriptase inhibitor can interact with MRP1, MRP2, and MRP3 in vitro. Inhibition of these ABC transporters was quantified by confocal laser-scanning microscopy using the 5-chloromethylfluorescein diacetate assay. With the exception of abacavir, which had no effect on MRP3, all the test compounds increased intracellular 5-chloromethylfluorescein fluorescence in a concentration-dependent manner, and this effect was observed in all the overexpressing cell lines but not in the parental cell line, indicating inhibition of MRP1, MRP2, and MRP3. In conclusion, the present study provides the first evidence for a significant and concentration-dependent inhibition of MRPs by NNRTI, NRTI, and tenofovir, which was most pronounced for delavirdine, efavirenz, and emtricitabine, suggesting that this might contribute to some of the known drug interactions impairing HIV therapy and also to the superior effectiveness of combination pharmacotherapy.Infections with the human immunodeficiency virus (HIV) are typically treated with drug combinations consisting of at least three different antiretroviral drugs. Essential components of this highly active antiretroviral therapy (HAART) are the HIV protease inhibitors (HPI), the non-nucleoside and nucleoside reverse transcriptase inhibitors (NNRTI and NRTI), and the nucleotide reverse transcriptase inhibitor tenofovir. Whereas this combination therapy substantially improves the clinical prognosis for patients infected with HIV, it concurrently increases the risk for drug-drug interactions (Piscitelli and Gallicano, 2001;de Maat et al., 2003).Many drug interactions with antiretrovirals, but by far not all and particularly not those with NRTI, occur at the level of different cytochrome P450 isozymes (Dasgupta and Okhuysen, 2001;Piscitelli and Gallicano, 2001;de Maat et al., 2003). Indeed, increasing evidence suggests that antiretrovirals may also modify activity and expression of active drug transport systems. Such interactions may determine drug absorption, elimination, and also drug distribution and reac...

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Brain Pharmacokinetics of Ganciclovir in Rats with Orthotopic BT4C Glioma

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