caa a22 4500 477125646 CHVBK 20180405111648.0 cr unu---uuuuu 170330e19970101xx s 000 0 eng 10.1023/A:1012091014242 doi (NATIONALLICENCE)springer-10.1023/A:1012091014242 Esterase-Sensitive Cyclic Prodrugs of Peptides: Evaluation of a Phenylpropionic Acid Promoiety in a Model Hexapeptide [Elektronische Daten] [Giovanni Pauletti, Sanjeev Gangwar, Binghe Wang, Ronald Borchardt] Purpose. To evaluate a cyclic phenylpropionic acid prodrug of a model hexapeptide (H-Trp-Ala-Gly-Gly-Asp-Ala-OH) as a novel approach to enhance the membrane permeation of a peptide and stabilize it to metabolism. Methods. Conversion to the linear hexapeptide was studied at 37°C in HBSS, pH 7.4, and in various biological milieus having measurable esterase activities. Transport and metabolism characteristics were assessed using the Caco-2 cell culture model. Results. In aqueous buffered solution, pH 7.4, the cyclic prodrug degraded quantitatively (t 1/2 = 1795 ± 289 min) to the linear hexapeptide and the lactone. Substantially faster degradation of the cyclic prodrug was observed in 90% human plasma (t 1/2 = 508 ± 24 min), and in homogenates of Caco-2 cells (t 1/2 = 940 ± 13 min), the rat intestinal mucosa (t 1/2 = 1286 ± 32 min), and rat liver (t 1/2 = 840 ± 42 min). Pretreatment of these biological 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 was significantly more stable than the hexapeptide and at least 71-fold more able to permeate (Papp = 1.21 ± 0.12 × 10−7 cm/s) than was the parent peptide (Papp ≤ 0.17 × 10−8 cm/s). In the presence of 0.1 mM palmitoyl-DL-carnitine, the transport rate of the cyclic prodrug (Papp = 2.19 × 10−6 cm/s) was 1250-fold greater than that of the linear hexapeptide. Conclusions. Preparation of a cyclic peptide using a phenylpropionic acid 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. Plenum Publishing Corporation, 1997 esterase-sensitive prodrug nationallicence chemical and enzymatic stability nationallicence peptide delivery nationallicence Caco-2 cells nationallicence palmitoyl-DL-carnitine nationallicence membrane permeability nationallicence Pauletti Giovanni Department of Pharmaceutical Chemistry, The University of Kansas, 2095 Constant Ave., 66047, Lawrence, Kansas aut Gangwar Sanjeev Department of Pharmaceutical Chemistry, The University of Kansas, 2095 Constant Ave., 66047, Lawrence, Kansas aut Wang Binghe Department of Chemistry, North Carolina State University, 27695-8204, Raleigh, North Carolina aut Borchardt Ronald Department of Pharmaceutical Chemistry, The University of Kansas, 2095 Constant Ave., 66047, Lawrence, Kansas aut Pharmaceutical Research Kluwer Academic Publishers-Plenum Publishers 14/1(1997-01-01), 11-17 0724-8741 14:1<11 1997 14 11095 https://doi.org/10.1023/A:1012091014242 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1023/A:1012091014242 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Pauletti Giovanni Department of Pharmaceutical Chemistry, The University of Kansas, 2095 Constant Ave., 66047, Lawrence, Kansas aut NATIONALLICENCE 700 1- Gangwar Sanjeev Department of Pharmaceutical Chemistry, The University of Kansas, 2095 Constant Ave., 66047, Lawrence, Kansas aut NATIONALLICENCE 700 1- Wang Binghe Department of Chemistry, North Carolina State University, 27695-8204, Raleigh, North Carolina aut NATIONALLICENCE 700 1- Borchardt Ronald Department of Pharmaceutical Chemistry, The University of Kansas, 2095 Constant Ave., 66047, Lawrence, Kansas aut NATIONALLICENCE 773 0- Pharmaceutical Research Kluwer Academic Publishers-Plenum Publishers 14/1(1997-01-01), 11-17 0724-8741 14:1<11 1997 14 11095 Metadata rights reserved Springer special CC-BY-NC licence nationallicence SWISSBIB 474098427 BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer