ArticlePharmaceutical research2005
Floxuridine amino acid ester prodrugs: enhancing Caco-2 permeability and resistance to glycosidic bond metabolism.
Article in Pharmaceutical research, 2005. 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, 77 citations in OpenAlex.
- Article
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- Biofunctional Excipients: Their Emerging Role in Overcoming the Inherent Poor Biopharmaceutical Characteristics of Drugs.Pharmaceutics · 2025Review
- Pharmacokinetic Evaluation of Neutral Sphinghomyelinase2 (nSMase2) Inhibitor Prodrugs in Mice and Dogs.Pharmaceutics · 2024Article
- Investigating the Transepithelial Transport and Enzymatic Stability of Lactononadecapeptide (NIPPLTQTPVVVPPFLQPE), a 19-Amino Acid Casein-Derived Peptide in Caco-2 Cells.Journal of agricultural and food chemistry · 2024Article
- Molecular Idiosyncratic Toxicology of Drugs in the Human Liver Compared with Animals: Basic Considerations.International journal of molecular sciences · 2023Review
- Transporter-Mediated Drug Delivery.Molecules (Basel, Switzerland) · 2023Review
- Mechanism of idiosyncratic drug induced liver injury (DILI): unresolved basic issues.Annals of translational medicine · 2021Review
- Development of a Split Esterase for Protein-Protein Interaction-Dependent Small-Molecule Activation.ACS central science · 2019Article
- Amino Acids in the Development of Prodrugs.Molecules (Basel, Switzerland) · 2018Review
- Potential Development of Tumor-Targeted Oral Anti-Cancer Prodrugs: Amino Acid and Dipeptide Monoester Prodrugs of Gemcitabine.Molecules (Basel, Switzerland) · 2017Article
- Metabolism, Biochemical Actions, and Chemical Synthesis of Anticancer Nucleosides, Nucleotides, and Base Analogs.Chemical reviews · 2016Review
- Synthesis and in vitro evaluation of bile acid prodrugs of floxuridine to target the liver.International journal of pharmaceutics · 2014Article
- Amino Acid Prodrugs: An Approach to Improve the Absorption of HIV-1 Protease Inhibitor, Lopinavir.Pharmaceuticals (Basel, Switzerland) · 2014Article
- The development of orally administrable gemcitabine prodrugs with D-enantiomer amino acids: enhanced membrane permeability and enzymatic stability.European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V · 2014Article
- Application of activated nucleoside analogs for the treatment of drug-resistant tumors by oral delivery of nanogel-drug conjugates.Journal of controlled release : official journal of the Controlled Release Society · 2013Article
- The feasibility of enzyme targeted activation for amino acid/dipeptide monoester prodrugs of floxuridine; cathepsin D as a potential targeted enzyme.Molecules (Basel, Switzerland) · 2012Article
- Enhancing the intestinal membrane permeability of zanamivir: a carrier mediated prodrug approach.Molecular pharmaceutics · 2011Article
- Potential of amino acid/dipeptide monoester prodrugs of floxuridine in facilitating enhanced delivery of active drug to interior sites of tumors: a two-tier monolayer in vitro study.Pharmaceutical research · 2011Article
Corrections and comments
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
Abstract
purposeThe aim of this study was to synthesize amino acid ester prodrugs of 5-fluoro-2'-deoxyuridine (floxuridine) to enhance intestinal absorption and resistance to glycosidic bond metabolism.
methodsAmino acid ester prodrugs were synthesized and examined for their hydrolytic stability in human plasma, in Caco-2 cell homogenates, and in the presence of thymidine phosphorylase. Glycyl-L: -sarcosine uptake inhibition and direct uptake studies with HeLa/PEPT1 cells [HeLa cells overexpressing oligopeptide transporter (PEPT1)] were conducted to determine PEPT1-mediated transport and compared with permeability of the prodrugs across Caco-2 monolayers.
resultsIsoleucyl prodrugs exhibited the highest chemical and enzymatic stability. The prodrugs enhanced the stability of the glycosidic bond of floxuridine. Thymidine phosphorylase rapidly cleaved floxuridine to 5-fluorouracil, whereas with the prodrugs no detectable glycosidic bond cleavage was observed. The 5'-L: -isoleucyl and 5'-L: -valyl monoester prodrugs exhibited 8- and 19-fold PEPT1-mediated uptake enhancement in HeLa/PEPT1 cells, respectively. Uptake enhancement in HeLa/PEPT1 cells correlated highly with Caco-2 permeability for all prodrugs tested. Caco-2 permeability of 5'-L: -isoleucyl and 5'-L: -valyl prodrugs was 8- to 11-fold greater compared with floxuridine.
conclusionsAmino acid ester prodrugs such as isoleucyl floxuridine that exhibit enhanced Caco-2 transport and slower rate of enzymatic activation to parent, and that are highly resistant to metabolism by thymidine phosphorylase may improve oral delivery and therapeutic index of floxuridine.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.