Molecular assessment of the potential for renal drug interactions between tenofovir and HIV protease inhibitors.

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 (Pls) with tenofovir disoproxil fumarate (TDF), an oral prodrug of TFV, has been shown to increase systemic levels of TFV, leading to a hypothesis that Pls may affect tubular secretion of TFV and potentially alter the renal safety of TDF. Methods: The effect of Pls 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 (C max ) all Pls showed <20% inhibition of TFV transport by hOAT1. hOAT3 was more sensitive to Pls with ritonavir (RTV) and lopinavir being the most potent inhibitors of TFV transport (62% and 37% inhibition, respectively, at their C max ). In the absence of human serum, RTV at concentrations exceeding its therapeutic C max also exhibited a minor effect on the cellular efflux of TFV by MRP4 (<30% inhibition at 20 μM). However, no effects of Pls on hOAT1, hOAT3 or MRP4 were detected in the presence of human serum with the exception of RTV that inhibited hOAT3 by approximately 35% at its C max . In addition, Pls did not affect the cytotoxicity of TFV or TDF in MRP4- or MRP2-overexpressing cells. Conclusion: These data indicate a low potential of Pls to interfere with the active tubular secretion of TFV and to alter the clinical renal safety profile of TDF.