ArticleAntimicrobial agents and chemotherapy2014
Metabolism and pharmacokinetics of the anti-hepatitis C virus nucleotide prodrug GS-6620.
Article in Antimicrobial agents and chemotherapy, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.
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Who cites it
28 citing papers in PubMed, 46 citations in OpenAlex.
- Sofosbuvir and Ribavirin Liver Pharmacokinetics in Patients Infected with Hepatitis C Virus.Antimicrobial agents and chemotherapy · 2018Trial
- NS5-targeting nucleoside analogs inhibit dengue virus and other flaviviruses.PLoS pathogens · 2026Article
- The activation cascade of the broad-spectrum antiviral bemnifosbuvir characterized at atomic resolution.PLoS biology · 2024Article
- Prodrugs of a 1-Hydroxy-2-oxopiperidin-3-yl Phosphonate Enolase Inhibitor for the Treatment ofJournal of medicinal chemistry · 2022Article
- The Novel Nucleoside Analogue ProTide NUC-7738 Overcomes Cancer Resistance MechanismsClinical cancer research : an official journal of the American Association for Cancer Research · 2021Article
- Liposomal remdesivir inhalation solution for targeted lung delivery as a novel therapeutic approach for COVID-19.Asian journal of pharmaceutical sciences · 2021Article
- Why Remdesivir Failed: Preclinical Assumptions Overestimate the Clinical Efficacy of Remdesivir for COVID-19 and Ebola.Antimicrobial agents and chemotherapy · 2021Article
- Combination Therapy with Fluoxetine and the Nucleoside Analog GS-441524 Exerts Synergistic Antiviral Effects against Different SARS-CoV-2 Variants In Vitro.Pharmaceutics · 2021Article
- Key Metabolic Enzymes Involved in Remdesivir Activation in Human Lung Cells.Antimicrobial agents and chemotherapy · 2021Article
- A Biochemical Perspective of the Nonstructural Proteins (NSPs) and the Spike Protein of SARS CoV-2.The protein journal · 2021Review
- Tissue-Specific Proteomics Analysis of Anti-COVID-19 Nucleoside and Nucleotide Prodrug-Activating Enzymes Provides Insights into the Optimization of Prodrug Design and Pharmacotherapy Strategy.ACS pharmacology & translational science · 2021Article
- CETSA MS Profiling for a Comparative Assessment of FDA-Approved Antivirals Repurposed for COVID-19 Therapy Identifies TRIP13 as a Remdesivir Off-Target.SLAS discovery : advancing life sciences R & D · 2021Article
- Synergistic and Antagonistic Drug Combinations against SARS-CoV-2.Molecular therapy : the journal of the American Society of Gene Therapy · 2021Article
- Antiviral and Antimicrobial Nucleoside Derivatives: Structural Features and Mechanisms of Action.Molecular biology · 2021Article
- A Cyclic Phosphoramidate Prodrug of 2'-Deoxy-2'-Fluoro-2'-Antimicrobial agents and chemotherapy · 2020Article
- The Enzyme-Free Release of Nucleotides from Phosphoramidates Depends Strongly on the Amino Acid.Angewandte Chemie (International ed. in English) · 2020Article
- Metabolic Efficacy of Phosphate Prodrugs and the Remdesivir Paradigm.ACS pharmacology & translational science · 2020Review
- Advantages of the Parent Nucleoside GS-441524 over Remdesivir for Covid-19 Treatment.ACS medicinal chemistry letters · 2020Article
- Discovery of Synergistic and Antagonistic Drug Combinations against SARS-CoV-2 In Vitro.bioRxiv : the preprint server for biology · 2020Article
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13 authors at 1 institution in 1 country.
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No grant is acknowledged in the PubMed record.
Abstract
The anti-hepatitis C virus nucleotide prodrug GS-6620 employs a double-prodrug approach, with l-alanine-isopropyl ester and phenol moieties attached to the 5'-phosphate that release the nucleoside monophosphate in hepatocytes and a 3'-isobutyryl ester added to improve permeability and oral bioavailability. Consistent with the stability found in intestinal homogenates, following oral administration, intact prodrug levels in blood plasma were the highest in dogs, followed by monkeys, and then were the lowest in hamsters. In contrast, liver levels of the triphosphate metabolite at the equivalent surface area-adjusted doses were highest in hamsters, followed by in dogs and monkeys. Studies in isolated primary hepatocytes suggest that relatively poor oral absorption in hamsters and monkeys was compensated for by relatively efficient hepatocyte activation. As intestinal absorption was found to be critical to the effectiveness of GS-6620 in nonclinical species, stomach pH, formulation, and food effect studies were completed in dogs. Consistent with in vitro absorption studies in Caco-2 cells, the absorption of GS-6620 was found to be complex and highly dependent on concentration. Higher rates of metabolism were observed at lower concentrations that were unable to saturate intestinal efflux transporters. In first-in-human clinical trials, the oral administration of GS-6620 resulted in poor plasma exposure relative to that observed in dogs and in large pharmacokinetic and pharmacodynamic variabilities. While a double-prodrug approach, including a 3'-isobutyryl ester, provided higher intrinsic intestinal permeability, this substitution appeared to be a metabolic liability, resulting in extensive intestinal metabolism and relatively poor oral absorption in humans.
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