Novel nucleotide human immunodeficiency virus reverse transcriptase inhibitor GS-9148 with a low nephrotoxic potential: characterization of renal transport and accumulation.
Accumulation of antiviral nucleotides in renal proximal tubules is controlled by their basolateral uptake via the human renal organic anion transporters type 1 (hOAT1) and 3 (hOAT3) and apical efflux via the multidrug resistance protein 4 (MRP4). GS-9148 is a novel ribose-modified nucleotide human immunodeficiency virus (HIV) reverse transcriptase inhibitor, and its oral prodrug GS-9131 is currently being evaluated in the clinic as an anti-HIV agent. To assess the potential of GS-9148 for nephrotoxicity, its mechanism of renal transport, cytotoxicity, and renal accumulation were explored in vitro and in vivo. In comparison with the acyclic nucleotides cidofovir, adefovir, and tenofovir, GS-9148 showed 60- to 100-fold lower efficiency of transport (V(max)/K(m)) by hOAT1 and was 20- to 300-fold less cytotoxic in cells overexpressing hOAT1, indicating its lower hOAT1-mediated intracellular accumulation and reduced intrinsic cytotoxicity. GS-9148 was also relatively inefficiently transported by hOAT3. Similar to acyclic nucleotides, GS-9148 was a substrate for MRP4 as evidenced by its reduced intracellular retention in cells overexpressing the efflux pump. Consistent with these molecular observations, GS-9148 was inefficiently taken up by fresh human renal cortex tissue in vitro and showed a limited accumulation in kidneys in vivo following oral administration of [(14)C]GS-9131 to dogs. Compared to acyclic nucleotide analogs, GS-9148 was also found to have lower net active tubular secretion in dogs. Collectively, these results suggest that GS-9148 exhibits a low potential for renal accumulation and nephrotoxicity.
Cihlar
Tomas
T
Gilead Sciences, Inc, Foster City, California 94404, USA. tomas.cihlar@gilead.com
Laflamme
Genevieve
G
Fisher
Robyn
R
Carey
Anne C
AC
Vela
Jennifer E
JE
Mackman
Richard
R
Ray
Adrian S
AS
D000225:Adenine / Q000031:analogs & derivatives / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D016466:CHO Cells; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D000077404:Cidofovir; D006224:Cricetinae; D003412:Cricetulus; D003596:Cytosine / Q000031:analogs & derivatives / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D006151:Guanosine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors*; D006801:Humans; D066298:In Vitro Techniques; D007668:Kidney / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D027362:Organic Anion Transport Protein 1 / Q000235:genetics / Q000378:metabolism; D029362:Organic Anion Transporters, Sodium-Independent / Q000235:genetics / Q000378:metabolism; D063065:Organophosphonates / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D018894:Reverse Transcriptase Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology*; D000068698:Tenofovir
C519972:GS-9131; D027362:Organic Anion Transport Protein 1; D029362:Organic Anion Transporters, Sodium-Independent; D063065:Organophosphonates; D018894:Reverse Transcriptase Inhibitors; C114338:organic anion transport protein 3; D006151:Guanosine; C053001:adefovir; D003596:Cytosine; D000068698:Tenofovir; C527398:GS-9148; D054303:HIV Reverse Transcriptase; D000225:Adenine; D000077404:Cidofovir