Background:  GS-9148 is a novel ribose-modified NRTI with a favorable in vitro activity profile against HIV-1 strains resistant to multiple NRTI. Its oral prodrug, GS-9131, efficiently delivers GS-9148 into peripheral lymphocytes in vivo and is currently under clinical evaluation. Since the nephrotoxicity of clinically used antiviral nucleotides is linked to their active accumulation in renal proximal tubules via organic anion transporters, we characterized the renal transport of GS-9148 in comparison with acyclic nucleotides cidofovir, adefovir, and tenofovir.

Methods:  Cytotoxicity in vitro was assessed in primary human renal proximal tubule cells (RPTEC). Kinetics of renal transport and its effect on the cytotoxicity of nucleotides was characterized in CHO and BHK cells stably transfected with human renal organic anion transporter type 1 (hOAT1) and 3 (hOAT3), respectively. Precision-cut fresh tissue slices were used to measure the in vitro accumulation of nucleotides in human renal cortex. In vivo renal accumulation was determined following the oral administration of [¹⁴C]GS-9131 or [¹⁴C]tenofovir (TDF) to beagle dogs.

Results:  Similar to TDF, GS-9148 exhibited reduced cytotoxicity in RPTEC (CC₅₀ > 2000 μM) compared to cidofovir and adefovir (CC₅₀ = 260 and 495 μM, respectively). Notably, GS-9148 showed 5- to 10-fold lower affinity (K_m) for hOAT1 and 60- to 100-fold lower efficiency of transport (V_max/K_m) by hOAT1 than the comparative acyclic nucleotides. GS-9148 was also 300-, 100-, and 20-fold less cytotoxic than adefovir, cidofovir and tenofovir, respectively, in cells overexpressing hOAT1, indicating a substantially lower steady-state hOAT1-specific intracellular accumulation of GS-9148. The transport of GS-9148 by hOAT3, a secondary pathway for renal uptake of nucleotides, was 2- and 6-fold lower than that of TDF and adefovir, respectively. Finally, experiments with fresh human renal tissue indicated 5-fold lower probenecid-sensitive uptake of GS-9148 into kidney cortex compared to TDF; a similar difference was observed in the renal accumulation of radio-labeled material following oral administration of GS-9131 and TDF to dogs.  

Conclusions:  The results of this study demonstrate a markedly less effective renal transport of GS-9148 compared with cidofovir, adefovir, and TDF, suggesting a low potential for nephrotoxicity.