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 Für Pharmazeutische Verfahrenstechnik E.V
Yasuhiro TsumeGordon L Amidon

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'-...Continue Reading

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Citations

Jun 9, 2015·Journal of Pharmaceutical Sciences·Maureen D DonovanLawrence X Yu
Jul 15, 2015·International Journal of Pharmaceutics·Ravindra Dhar DubeyPrem N Gupta
May 17, 2018·Beilstein Journal of Organic Chemistry·Eirinaios I VrettosAndreas G Tzakos
Mar 10, 2020·Journal of Labelled Compounds & Radiopharmaceuticals·Zbigniew P KortylewiczJanina Baranowska-Kortylewicz
Oct 14, 2018·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Sungwoo HongHan-Joo Maeng
Jan 14, 2017·Frontiers in Microbiology·Eyal RosenIlana Kolodkin-Gal
Aug 11, 2017·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Yasuhiro TsumeGordon L Amidon
Nov 17, 2017·Cancers·Manoj Amrutkar, Ivar P Gladhaug
Sep 14, 2018·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Nuno ValeMaria João Gouveia
Jan 23, 2021·RSC Medicinal Chemistry·Cristiana CorreiaNuno Vale
Feb 26, 2021·European Journal of Pharmaceutics and Biopharmaceutics : Official Journal of Arbeitsgemeinschaft Für Pharmazeutische Verfahrenstechnik E.V·Utkarsh BhutaniSaptarshi Majumdar
Mar 21, 2020·Molecular Pharmaceutics·Vikram M ShenoyGordon L Amidon

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