PMID: 8956324Nov 1, 1996Paper

Esterase-sensitive cyclic prodrugs of peptides: evaluation of an acyloxyalkoxy promoiety in a model hexapeptide

Pharmaceutical Research
G M PaulettiR T Borchardt

Abstract

To 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. Conversion 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. In 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 pe...Continue Reading

Citations

Jul 16, 1999·The Journal of Peptide Research : Official Journal of the American Peptide Society·O S GudmundssonR T Borchardt
May 20, 2005·The Journal of Pharmacology and Experimental Therapeutics·Philip L LorenziGordon L Amidon
Jun 8, 2017·Drug Development and Industrial Pharmacy·Ožbej ZupančičAndreas Bernkop-Schnürch
Dec 1, 2001·Expert Opinion on Biological Therapy·G S TirucheraiA K Mitra
Oct 22, 2002·The Journal of Pharmacology and Experimental Therapeutics·Jerry Z YangRonald T Borchardt
May 20, 2003·The Journal of Peptide Research : Official Journal of the American Peptide Society·H T HeT J Siahaan
Jul 16, 1999·The Journal of Peptide Research : Official Journal of the American Peptide Society·B WangR T Borchardt
Feb 6, 2020·AAPS PharmSciTech·Nermin E ElerakyGiovanni M Pauletti
Jul 3, 2002·Experimental Biology and Medicine·Lauren R PlagemanKenneth A Skau
Feb 14, 2002·Chemical Reviews·A Sood, R Panchagnula
Apr 3, 1999·Journal of Pharmaceutical Sciences·B H Stewart, O H Chan
Apr 9, 2005·International Journal of Pharmaceutics·Nazila Salamat-Miller, Thomas P Johnston
Nov 8, 2003·The Journal of Organic Chemistry·Wenxin Gu, Richard B Silverman

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