BACKGROUND: Tenofovir alafenamide (TAF) is a novel prodrug of tenofovir that shows enhanced antiretroviral effect and reduced plasma tenofovir exposures at approximately one-tenth the clinically approved dose of tenofovir disoproxil fumarate (TDF). Tenofovir released from TDF undergoes active renal secretion via organic anion transporters (OAT1 and OAT3), leading to higher exposure of renal proximal tubules to tenofovir and a potential for renal adverse effects in a small subset of TDF-treated patients. Here, we evaluate the interaction of TAF with OAT1 and OAT3 to assess the potential for its active accumulation in proximal tubules. METHODS: OAT-mediated transport and cytotoxicity (CC50) of TAF and tenofovir were assessed in cells expressing OATs and compared with matched transporter-null cells. RESULTS: While OAT1 and OAT3 expression increased tenofovir cellular uptake by >70-fold and 8.2-fold, respectively, the expression of either OAT did not significantly change TAF intracellular accumulation under identical conditions. In addition, although tenofovir was significantly more cytotoxic in OAT1- and OAT3-expressing cells (>21 and >3.6 fold change in CC50 values, respectively), TAF in vitro cytotoxicity showed little to no change upon overexpression of either renal transporter (0.5-3.5 fold change in CC50). CONCLUSIONS: Unlike tenofovir, TAF does not interact with renal transporters OAT1 or OAT3 and exhibits no OAT-dependent cytotoxicity. TAF is thus unlikely to actively accumulate in renal proximal tubules in an OAT-dependent manner, supporting the potential for an improved renal safety profile.
BACKGROUND:Tenofovir alafenamide (TAF) is a novel prodrug of tenofovir that shows enhanced antiretroviral effect and reduced plasma tenofovir exposures at approximately one-tenth the clinically approved dose of tenofovir disoproxil fumarate (TDF). Tenofovir released from TDF undergoes active renal secretion via organic anion transporters (OAT1 and OAT3), leading to higher exposure of renal proximal tubules to tenofovir and a potential for renal adverse effects in a small subset of TDF-treated patients. Here, we evaluate the interaction of TAF with OAT1 and OAT3 to assess the potential for its active accumulation in proximal tubules. METHODS:OAT-mediated transport and cytotoxicity (CC50) of TAF and tenofovir were assessed in cells expressing OATs and compared with matched transporter-null cells. RESULTS: While OAT1 and OAT3 expression increased tenofovir cellular uptake by >70-fold and 8.2-fold, respectively, the expression of either OAT did not significantly change TAF intracellular accumulation under identical conditions. In addition, although tenofovir was significantly more cytotoxic in OAT1- and OAT3-expressing cells (>21 and >3.6 fold change in CC50 values, respectively), TAF in vitro cytotoxicity showed little to no change upon overexpression of either renal transporter (0.5-3.5 fold change in CC50). CONCLUSIONS: Unlike tenofovir, TAF does not interact with renal transporters OAT1 or OAT3 and exhibits no OAT-dependent cytotoxicity. TAF is thus unlikely to actively accumulate in renal proximal tubules in an OAT-dependent manner, supporting the potential for an improved renal safety profile.
Authors: Pamela Hummert; Teresa L Parsons; Laura M Ensign; Thuy Hoang; Mark A Marzinke Journal: J Pharm Biomed Anal Date: 2018-02-08 Impact factor: 3.935
Authors: James M Mikula; Maura M Manion; Frank Maldarelli; Lucila M Suarez; Jaha F Norman-Wheeler; Alex G Ober; Robin L Dewar; Jeffrey B Kopp; H Clifford Lane; Alice K Pau Journal: Antivir Ther Date: 2016-03-08