Tenofovir alafenamide is not a substrate for renal organic anion transporters (OATs) and does not exhibit OAT-dependent cytotoxicity.
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.
Gilead Sciences, Biology Department, Foster City, CA, USA.
Rujuta A
RA
Bam
Stephen R
SR
Yant
Tomas
T
Cihlar
D000225:Adenine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D000409:Alanine; D000998:Antiviral Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D001692:Biological Transport; D002460:Cell Line; D002478:Cells, Cultured; D015870:Gene Expression; D006801:Humans; D007687:Kidney Tubules, Proximal / Q000378:metabolism*; D027362:Organic Anion Transport Protein 1 / Q000235:genetics / Q000378:metabolism; D027361:Organic Anion Transporters / Q000235:genetics / Q000378:metabolism*; D029362:Organic Anion Transporters, Sodium-Independent / Q000235:genetics / Q000378:metabolism; D000068698:Tenofovir / Q000031:analogs & derivatives
D000998:Antiviral Agents; D027362:Organic Anion Transport Protein 1; D027361:Organic Anion Transporters; D029362:Organic Anion Transporters, Sodium-Independent; C114338:organic anion transport protein 3; D000068698:Tenofovir; C442442:tenofovir alafenamide; D000225:Adenine; D000409:Alanine