ArticleEuropean journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V2014
The development of orally administrable gemcitabine prodrugs with D-enantiomer amino acids: enhanced membrane permeability and enzymatic stability.
Article in European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed, 42 citations in OpenAlex.
- Synthesis, characterization, and anticancer evaluation of 1,3-bistetrahydrofuran-2yl-5-FU as a potential agent for pancreatic cancer.BMC cancer · 2022Article
- Pharmacokinetics of gemcitabine and its amino acid ester prodrug following intravenous and oral administrations in mice.Biochemical pharmacology · 2020Article
- Radiolabeled (R)-(-)-5-iodo-3'-O-[2-(ε-guanidinohexanoyl)-2-phenylacetyl]-2'-deoxyuridine: A new theranostic for neuroblastoma.Journal of labelled compounds & radiopharmaceuticals · 2020Article
- Development of potent CPP6-gemcitabine conjugates against human prostate cancer cell line (PC-3).RSC medicinal chemistry · 2020Article
- Mechanisms of gemcitabine oral absorption as determined by in situ intestinal perfusions in mice.Biochemical pharmacology · 2019Article
- Synthesis of Gemcitabine-Threonine Amide Prodrug Effective on Pancreatic Cancer Cells with Improved Pharmacokinetic Properties.Molecules (Basel, Switzerland) · 2018Article
- Amino Acids in the Development of Prodrugs.Molecules (Basel, Switzerland) · 2018Review
- Thymoquinone synergizes gemcitabine anti-breast cancer activity via modulating its apoptotic and autophagic activities.Scientific reports · 2018Article
- On the design principles of peptide-drug conjugates for targeted drug delivery to the malignant tumor site.Beilstein journal of organic chemistry · 2018Review
- Pancreatic Cancer Chemoresistance to Gemcitabine.Cancers · 2017Review
- Potential Development of Tumor-Targeted Oral Anti-Cancer Prodrugs: Amino Acid and Dipeptide Monoester Prodrugs of Gemcitabine.Molecules (Basel, Switzerland) · 2017Article
- Encapsulating a Hydrophilic Chemotherapeutic into Rod-like Nanoparticles of a Genetically Encoded Asymmetric Triblock Polypeptide Improves its Efficacy.Advanced functional materials · 2017Article
- Metabolism, Biochemical Actions, and Chemical Synthesis of Anticancer Nucleosides, Nucleotides, and Base Analogs.Chemical reviews · 2016Review
- Eradication ofFrontiers in microbiology · 2016Article
- Amino Acid Derivatives as Palmitoylethanolamide Prodrugs: Synthesis, In Vitro Metabolism and In Vivo Plasma Profile in Rats.PloS one · 2015Article
Corrections and comments
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Authors and funding
5 authors at 2 institutions in 2 countries.
Funding
Abstract
Gemcitabine prodrugs with D- and L-configuration amino acids were synthesized and their chemical stability in buffers, resistance to glycosidic bond metabolism, enzymatic activation, permeability in Caco-2 cells and mouse intestinal membrane, anti-proliferation activity in cancer cell were determined and compared to that of parent drug, gemcitabine. Prodrugs containing D-configuration amino acids were enzymatically more stable than ones with L-configuration amino acids. The activation of all gemcitabine prodrugs was 1.3-17.6-fold faster in cancer cell homogenate than their hydrolysis in buffer, suggesting enzymatic action. The enzymatic activation of amino acid monoester prodrugs containing D-configuration amino acids in cell homogenates was 2.2-10.9-fold slower than one of amino acid monoester prodrugs with L-configuration amino acids. All prodrugs exhibited enhanced resistance to glycosidic bond metabolism by thymidine phosphorylase compared to parent gemcitabine. Gemcitabine prodrugs showed superior the effective permeability in mouse jejunum to gemcitabine. More importantly, the high plasma concentration of d-amino acid gemcitabine prodrugs was observed more than one of L-amino acid gemcitabine prodrugs. In general, the 5'-mono-amino acid monoester gemcitabine prodrugs exhibited higher permeability and uptake than their parent drug, gemcitabine. Cell proliferation assays in AsPC-1 pancreatic ductal cell line indicated that gemcitabine prodrugs were more potent than their parent drug, gemcitabine. The transport and enzymatic profiles of 5'-D-valyl-gemcitabine and 5'-D-phenylalanyl-gemcitabine suggest their potential for increased oral uptake and delayed enzymatic bioconversion as well as enhanced uptake and cytotoxic activity in cancer cells, would facilitate the development of oral dosage form for anti-cancer agents and, hence, improve the quality of life for the cancer patients.
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