Transport of levovirin prodrugs in the human intestinal Caco-2 cell line

Journal of Pharmaceutical Sciences
Fujun LiTom Alfredson

Abstract

The transport of 10 amino acid ester prodrugs of levovirin (LVV) was investigated in the human intestinal Caco-2 cell line in order to overcome the poor oral bioavailability of LVV, an investigational drug for the treatment of hepatitis C infection. The prodrugs were designed to improve the permeability of LVV across the intestinal epithelium by targeting the di/tri-peptide carrier, PepT1. Caco-2 cell monolayers were employed to study the transport and hydrolysis properties of the prodrugs. Among all mono amino acid ester prodrugs studied, the LVV-5'-(L)-valine prodrug (R1518) exhibited the maximum increase (48-fold) in permeability with nearly complete conversion to LVV within 1 h. Di-amino acid esters did not offer significant enhancement in permeability comparing with mono amino acid esters and exhibited slower conversion to LVV in Caco2 cell monolayers. Pharmacokinetic screening studies of the prodrugs in rats yielded the highest fold increase (6.9-fold) of AUC with R1518 and in general displayed a similar trend to that observed in increases of permeability in Caco-2 cells. Mechanisms involved in the Caco-2 cell transport of R1518 were also investigated. Results of bi-directional transport studies support the involvement of...Continue Reading

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Citations

Mar 13, 2009·AAPS PharmSciTech·Erina Pretorius, Patrick J D Bouic
Aug 19, 2007·Journal of Pharmaceutical Sciences·Fujun LiTom Alfredson
Mar 24, 2012·Drug Development and Industrial Pharmacy·Jucimary V SantosLuís A E Batista de Carvalho
Apr 25, 2008·Expert Opinion on Drug Metabolism & Toxicology·Huadong SunK Sandy Pang
Jan 23, 2013·Journal of Pharmacological and Toxicological Methods·André Bersani DezaniCristina Helena Dos Reis Serra
Jan 10, 2013·European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences·J M ReisC H R Serra
Mar 10, 2016·Journal of Pharmaceutical Sciences·Navid GoodarziJennifer B Dressman
Jul 24, 2007·European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences·Annegret BiegelIris Thondorf
Feb 3, 2011·Medicinal Research Reviews·Pedro Cano-Soldado, Marçal Pastor-Anglada
Jan 12, 2012·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·Eun-Young KwakChang-Koo Shim
Apr 18, 2015·Journal of Controlled Release : Official Journal of the Controlled Release Society·Haiyan GuoYanjiao Wang
Nov 5, 2013·European Journal of Pharmaceutics and Biopharmaceutics : Official Journal of Arbeitsgemeinschaft Für Pharmazeutische Verfahrenstechnik E.V·C MarkopoulosG Imanidis
May 8, 2016·Advanced Drug Delivery Reviews·M Sánchez-NavarroM Teixidó
Jun 21, 2016·Journal of Pharmaceutical Sciences·Teruo Murakami
Apr 18, 2008·The Journal of Pharmacy and Pharmacology·Matthias BrandschEva Bosse-Doenecke
Apr 8, 2020·Asian Journal of Pharmaceutical Sciences·Gang WangYang Wang
Feb 2, 2022·Drug Development Research·Athar HusainJiaur R Gayen

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