ArticleAntimicrobial agents and chemotherapy2009
Novel nucleotide human immunodeficiency virus reverse transcriptase inhibitor GS-9148 with a low nephrotoxic potential: characterization of renal transport and accumulation.
Article in Antimicrobial agents and chemotherapy, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed, 55 citations in OpenAlex.
- Understanding adefovir pharmacokinetics as a component of a transporter phenotyping cocktail.European journal of clinical pharmacology · 2024Article
- Article
- Focus on recently developed assays for detection of resistance/sensitivity to reverse transcriptase inhibitors.Applied microbiology and biotechnology · 2018Review
- Emerging reverse transcriptase inhibitors for HIV-1 infection.Expert opinion on emerging drugs · 2018Review
- Xenobiotic transporters and kidney injury.Advanced drug delivery reviews · 2017Review
- Tenofovir Disoproxil Fumarate Is a New Substrate of ATP-Binding Cassette Subfamily C Member 11.Antimicrobial agents and chemotherapy · 2017Article
- Brincidofovir Is Not a Substrate for the Human Organic Anion Transporter 1: A Mechanistic Explanation for the Lack of Nephrotoxicity Observed in Clinical Studies.Therapeutic drug monitoring · 2016Article
- A Human Renal Proximal Tubule Cell Line with Stable Organic Anion Transporter 1 and 3 Expression Predictive for Antiviral-Induced Toxicity.The AAPS journal · 2016Article
- Entecavir Interacts with Influx Transporters hOAT1, hCNT2, hCNT3, but Not with hOCT2: The Potential for Renal Transporter-Mediated Cytotoxicity and Drug-Drug Interactions.Frontiers in pharmacology · 2015Article
- Tenofovir-induced nephrotoxicity: incidence, mechanism, risk factors, prognosis and proposed agents for prevention.European journal of clinical pharmacology · 2014Review
- Evaluation of the effect of cobicistat on the in vitro renal transport and cytotoxicity potential of tenofovir.Antimicrobial agents and chemotherapy · 2013Article
- Update on tenofovir toxicity in the kidney.Pediatric nephrology (Berlin, Germany) · 2013Review
- Tenofovir renal proximal tubular toxicity is regulated by OAT1 and MRP4 transporters.Laboratory investigation; a journal of technical methods and pathology · 2011Article
- Mechanism of resistance to GS-9148 conferred by the Q151L mutation in HIV-1 reverse transcriptase.Antimicrobial agents and chemotherapy · 2011Article
- Tenofovir nephrotoxicity: 2011 update.AIDS research and treatment · 2011Article
- Assessment of the role of renal organic anion transporters in drug-induced nephrotoxicity.Toxins · 2010Review
- Tenofovir disoproxil fumarate: toxicity, toxicokinetics, and toxicogenomics analysis after 13 weeks of oral administration in mice.International journal of toxicologyArticle
Corrections and comments
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Authors and funding
7 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
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.
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