ArticlePharmaceutical research1998
Cellular uptake mechanism of amino acid ester prodrugs in Caco-2/hPEPT1 cells overexpressing a human peptide transporter.
Article in Pharmaceutical research, 1998. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 30 papers.
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Who cites it
30 citing papers in PubMed, 95 citations in OpenAlex.
- Intra- and interindividual variabilities of valacyclovir oral bioavailability and effect of coadministration of an hPEPT1 inhibitor.Antimicrobial agents and chemotherapy · 2003Trial
- Parameterization of Physiologically Based Biopharmaceutics Models: Workshop Summary Report.Molecular pharmaceutics · 2024Review
- Amino Acids in the Development of Prodrugs.Molecules (Basel, Switzerland) · 2018Review
- A small diversity library of α-methyl amide analogs of sulindac for probing anticancer structure-activity relationships.Bioorganic & medicinal chemistry letters · 2018Article
- Diverse amide analogs of sulindac for cancer treatment and prevention.Bioorganic & medicinal chemistry letters · 2017Article
- Specific expression of proton-coupled oligopeptide transporter 1 in primary hepatocarcinoma-a novel strategy for tumor-targeted therapy.Oncology letters · 2017Article
- Potential Development of Tumor-Targeted Oral Anti-Cancer Prodrugs: Amino Acid and Dipeptide Monoester Prodrugs of Gemcitabine.Molecules (Basel, Switzerland) · 2017Article
- D-amino acid-containing supramolecular nanofibers for potential cancer therapeutics.Advanced drug delivery reviews · 2017Review
- β-l-1-[5-(E-2-bromovinyl)-2-(hydroxymethyl)-1,3-(dioxolan-4-yl)] uracil (l-BHDU) prevents varicella-zoster virus replication in a SCID-Hu mouse model and does not interfere with 5-fluorouracil catabolism.Antiviral research · 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
- The dipeptide monoester prodrugs of floxuridine and gemcitabine-feasibility of orally administrable nucleoside analogs.Pharmaceuticals (Basel, Switzerland) · 2014Article
- Application of Caco-2 cell line in herb-drug interaction studies: current approaches and challenges.Journal of pharmacy & pharmaceutical sciences : a publication of the Canadian Society for Pharmaceutical Sciences, Societe canadienne des sciences pharmaceutiques · 2014Review
- Role of solute carriers in response to anticancer drugs.Molecular and cellular therapies · 2014Review
- The role and pathophysiological relevance of membrane transporter PepT1 in intestinal inflammation and inflammatory bowel disease.American journal of physiology. Gastrointestinal and liver physiology · 2012Review
- 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
- Simulations of the nonlinear dose dependence for substrates of influx and efflux transporters in the human intestine.The AAPS journal · 2009Article
- Enhanced absorption and growth inhibition with amino acid monoester prodrugs of floxuridine by targeting hPEPT1 transporters.Molecules (Basel, Switzerland) · 2008Article
- Regulation of the oligopeptide transporter, PEPT-1, in DSS-induced rat colitis.Digestive diseases and sciences · 2007Article
- Pharmacophore-based discovery of ligands for drug transporters.Advanced drug delivery reviews · 2006Review
Corrections and comments
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
Abstract
purposeThis study characterized the cellular uptake mechanism and hydrolysis of the amino acid ester prodrugs of nucleoside antiviral drugs in the transiently transfected Caco-2 cells overexpressing a human intestinal peptide transporter, hPEPT1 (Caco-2/hPEPT1 cells).
methodsAmino acid ester prodrugs of acyclovir and AZT were synthesized and their apical membrane permeability and hydrolysis were evaluated in Caco-2/hPEPT1 cells. The cellular uptake mechanism of prodrugs was investigated through the competitive inhibition study in Caco-2/hPEPT1 cells.
resultsL-Valyl ester of acyclovir (L-Val-ACV) was approximately ten fold more permeable across the apical membrane than acyclovir and four times more permeable than D-valyl ester of acyclovir (D-Val-ACV). Correspondingly, L-valyl ester of AZT (L- Val-AZT) exhibited three fold higher cellular uptake than AZT. Therefore, amino acid ester prodrugs significantly increased the cellular uptake of the parent drugs and exhibited the D,L-stereoselectivity. Furthermore, prodrugs were rapidly hydrolyzed to the parent drugs by the intracellular hydrolysis, following the apical membrane transport. In the inhibition studies, cephalexin and small dipeptides strongly inhibited the cellular uptake of L-Val-ACV while L-valine had no effect, indicating that the peptide transporter is primarily responsible for the apical membrane transport of L-Val-ACV. In addition, the cellular uptake of L-Val-ACV was five times higher in Caco-2/hPEPT1 cells than the uptake in the untransfected Caco-2 cells, implying the cellular uptake of L-Val-ACV was related to the enhancement of the peptide transport activity in Caco-2/hPEPT1 cells.
conclusionsCaco-2/hPEPT1 system is an efficient in vitro model for the uptake study of peptidyl derivatives. Amino acid ester prodrugs significantly improved the cellular uptake of the parent drugs via peptide transport mechanism and were rapidly converted to the active parent drugs by the intracellular hydrolysis.
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