ArticlePharmaceutical research1996
Esterase-sensitive cyclic prodrugs of peptides: evaluation of an acyloxyalkoxy promoiety in a model hexapeptide.
Article in Pharmaceutical research, 1996. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed, 67 citations in OpenAlex.
- Mammalian Esterase Activity: Implications for Peptide Prodrugs.Biochemistry · 2024Article
- Improvement on Permeability of Cyclic Peptide/Peptidomimetic: BackboneMarine drugs · 2021Review
- The protein kinase A pathway contributes to Hg2+-induced alterations in phosphorylation and subcellular distribution of occludin associated with increased tight junction permeability of salivary epithelial cell monolayers.The Journal of pharmacology and experimental therapeutics · 2008Article
- A modified coumarinic acid-based cyclic prodrug of an opioid peptide: its enzymatic and chemical stability and cell permeation characteristics.Pharmaceutical research · 2002Article
- Characterization of the efflux transporter(s) responsible for restricting intestinal mucosa permeation of an acyloxyalkoxy-based cyclic prodrug of the opioid peptide DADLE.Pharmaceutical research · 2002Article
- Pluronic P85 increases permeability of a broad spectrum of drugs in polarized BBMEC and Caco-2 cell monolayers.Pharmaceutical research · 1999Article
- Phenylpropionic acid-based cyclic prodrugs of opioid peptides that exhibit metabolic stability to peptidases and excellent cellular permeation.Pharmaceutical research · 1999Article
- Coumarinic acid-based cyclic prodrugs of opioid peptides that exhibit metabolic stability to peptidases and excellent cellular permeability.Pharmaceutical research · 1999Article
- Acyloxyalkoxy-based cyclic prodrugs of opioid peptides: evaluation of the chemical and enzymatic stability as well as their transport properties across Caco-2 cell monolayers.Pharmaceutical research · 1999Article
- A comparison of the bioconversion rates and the Caco-2 cell permeation characteristics of coumarin-based cyclic prodrugs and methylester-based linear prodrugs of RGD peptidomimetics.Pharmaceutical research · 1998Article
- Transport characteristics of peptidomimetics. Effect of the pyrrolinone bioisostere on transport across Caco-2 cell monolayers.Pharmaceutical research · 1998Article
- The effect of beta-turn structure on the passive diffusion of peptides across Caco-2 cell monolayers.Pharmaceutical research · 1997Article
- The effect of beta-turn structure on the permeation of peptides across monolayers of bovine brain microvessel endothelial cells.Pharmaceutical research · 1997Article
- Effect of size and charge on the passive diffusion of peptides across Caco-2 cell monolayers via the paracellular pathway.Pharmaceutical research · 1997Article
- Effect of restricted conformational flexibility on the permeation of model hexapeptides across Caco-2 cell monolayers.Pharmaceutical research · 1997Article
- Esterase-sensitive cyclic prodrugs of peptides: evaluation of a phenylpropionic acid promoiety in a model hexapeptide.Pharmaceutical research · 1997Article
- The effect of conformation on membrane permeability of an acyloxyalkoxy-linked cyclic prodrug of a model hexapeptide.Pharmaceutical research · 1996Article
Corrections and comments
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Authors and funding
6 authors at 1 institution in 1 country.
Funding
Abstract
purposeTo evaluate a cyclic acyloxyalkoxycarbamate prodrug of a model hexapeptide (H-Trp-Ala-Gly-Gly-Asp-Ala-OH) as a novel approach to enhance the membrane permeation of the peptide and stabilize it to metabolism.
methodsConversion to the linear hexapeptide was studied at 37 degrees C in aqueous buffered solutions and in various biological milieus having measurable esterase activities. Transport and metabolism characteristics were assessed using the Caco-2 cell culture model.
resultsIn buffered solutions the cyclic prodrug degraded chemically to the linear hexapeptide in stoichiometric amounts. Maximum stability was observed between pH 3-4. In 90% human plasma (t1/2 = 100 +/- 4 min) and in homogenates of the rat intestinal mucosa (t1/2 = 136 +/- 4 min) and rat liver (t1/2 = 65 +/- 3 min), the cyclic prodrug disappeared faster than in buffered solution, pH 7.4 (t1/2 = 206 +/- 11 min). Pretreatment of these media with paraoxon significantly decreased the degradation rate of the prodrug. When applied to the apical side of Caco-2 cell monolayers, the cyclic prodrug (t1/2 = 282 +/- 25 min) was significantly more stable than the hexapeptide (t1/2 = 14 min) and at least 76-fold more able to permeate (Papp = 1.30 +/- 0.15 x 10(-7) cm/s) than the parent peptide (Papp < or = 0.17 x 10(-8) cm/s).
conclusionsPreparation of a cyclic peptide using an acyloxyalkoxy promoiety reduced the lability of the peptide to peptidase metabolism and substantially increased its permeation through biological membranes. In various biological media the parent peptide was released from the prodrug by an apparent esterase-catalyzed reaction, sensitive to paraoxon inhibition.
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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.