Molecular Assessment of the Potential for Renal Drug Interactions between Tenofovir and HIV Protease Inhibitors

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Abstract
Background: Active renal secretion of tenofovir (TFV) across proximal tubules occurs via uptake by human organic anion transporters 1 and 3 (hOAT1 and hOAT3) coupled with efflux by multidrug resistance protein 4 (MRP4). Co-administration of some HIV protease inhibitors (PIs) with tenofovir disoproxil fumarate (TDF), an oral prodrug of TFV, has been shown to increase systemic levels of TFV, leading to a hypothesis that PIs may affect tubular secretion of TFV and potentially alter the renal safety of TDF. Methods: The effect of PIs on the transport of TFV by hOAT1, hOAT3 and MRP4 was assessed using in vitro cell-based transport models. Results: At concentrations equal to their therapeutic peak plasma levels (Cmax) all PIs showed max). In the absence of human serum, RTV at concentrations exceeding its therapeutic Cmax also exhibited a minor effect on the cellular efflux of TFV by MRP4 (max. In addition, PIs did not affect the cytotoxicity of TFV or TDF in MRP4- or MRP2-overexpressing cells. Conclusion: These data indicate a low potential of PIs to interfere with the active tubular secretion of TFV and to alter the clinical renal safety profile of TDF.