3rd International AIDS Society Conference on HIV Pathogenesis and Treatment Rio de Janeiro - July 24 - 27, 2005

MULTI-DRUG RESISTANCE PROTEIN-2 (MRP2) INHIBITION BY RITONAVIR INCREASES TENOFOVIR-ASSOCIATED RENAL EPITHELIAL CELL CYTOTOXICITY

IAS Conf HIV Pathog Treat 2005 Jul 24-27;3rd: Abstract No. WePe3.3C09

Louie S., Lam J., Neely M., Beringer P.
University of Southern California, Los Angeles, United States of America

INTRODUCTION: TFV is an acyclic nucleoside phosphonate (ANP) with minimal toxicity toward renal epithelial cells. Despite these data, clinical case reports have implicated the role of TFV in renal dysfunction, where the majority of cases were found in patients receiving both TFV and RTV. RTV is an inhibitor of MRP2, an efflux transporter, found abundantly on the apical side of renal epithelial cells. Since MRP2 is an important transporter of ANPs such as adefovir and cidofovir. We evaluated the impact of between TFV and MRP2 inhibitors such as RTV in renal cell epithelial cells (MDCK).

METHODS: MDCK and its overexpressing MRP2 (MDCK-MRP2) variant were used to determine whether inhibition of MRP2 increases TFV-associated renal cytotoxicity. MDCK wild type cells were exposed to TFV, RTV, or lopinavir (LPV) alone at concentrations ranging from 10 to 1000 µg/mL. In addition, TFV 10 µg/mL was combined with increasing concentrations of RTV, LPV, cyclosporine (CSA), and MK571. Proliferation of MDCK and MDCK-MRP2 cells, in the presence drugs, was evaluated by MTT assays after 24 hours of exposure.

RESULTS: The IC₅₀ values after 24 hours of exposure to TFV, RTV, and LPV alone were 1000, 130, and 130 mcg/mL, respectively. When TFV 10 mcg/mL was combined with either RTV or LPV, the IC₅₀ values were 99 or 96 mcg/mL, respectively. However, when TFV was combined with MK571 and CSA, IC₅₀ values were not achieved at the concentration tested. When MDCK-MRP2 was treated with the combination of TFV plus MRP2 inhibitors, IC₅₀ values were also not after 24 hours of exposure.

CONCLUSIONS: In the presence of TFV, inhibition of MRP2 inversely correlates with MDCK proliferation. However, MDCK-MRP2 cells are resistant to TFV even at the highest concentrations, suggesting that overexpression of MRP2 may prevent accumulation of TFV. This study suggests the role of MRP2 inhibition in TFV-associated.

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050724
Clinical | WePe3.3C09 | Stan Louie
Drug Interactions

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