caa a22 4500 477126537 CHVBK 20180405111651.0 cr unu---uuuuu 170330e19971201xx s 000 0 eng 10.1023/A:1012144232666 doi (NATIONALLICENCE)springer-10.1023/A:1012144232666 Rat Jejunal Permeability and Metabolism of μ-Selective Tetrapeptides in Gastrointestinal Fluids from Humans and Rats [Elektronische Daten] [Eva Krondahl, Achim Orzechowski, Gunilla Ekström, Hans Lennernäs] Purpose. To study intestinal transport and metabolism of three new μ-selective tetrapeptide enkephalin analogues, LEF537, LEF553 and TAPP These peptides are stabilized against enzymatic hydrolysis by having a D-aminoacid in position 2 and a blocked COOH-terminal. Methods. We used a single-pass perfusion technique to study the transport of the peptides in rat jejunum. To reduce luminal and/or brush-border metabolism during the perfusion we used protease inhibitors (Pefabloc® SC, bestatin and thiorphan). The rate of metabolism was studied by incubations in rat jejunal homogenate, rat jejunal fluid and human gastric and jejunal fluid with and without these inhibitors. Results. The jejunal permeabilities (Peff) of the peptides were 0.43−0.78 ⋅10−4 cm/s without inhibitors and 0.09−0.45 ⋅10−4 cm/s in presence of the inhibitors. All three peptides were rather rapidly degraded by enzymes in rat jejunal homogenate with half-lives of between 11.9 ± 0.5 and 31.7 ± 1.5 min. The addition of inhibitors to the homogenate prolonged the half-lives substantially for LEF553 (167 ± 35 min) and TAPP (147 ± 2 min), but only slightly for LEF537 (16.4 ± 0.5 min). LEF553 and TAPP were both hydrolyzed in rat and human jejunal fluid, while LEF537 was metabolized less in these fluids. When LEF553 and TAPP were incubated with intestinal fluid in the presence of inhibitors, metabolism was almost completely inhibited. There was no metabolism for any of the peptides in human gastric juice. Conclusions. The replacement of the terminal free carboxylic group with an amide group did not increase the stability of the peptides in jejunal tissue enough to allow successful oral drug delivery. Plenum Publishing Corporation, 1997 enkephalin analogues nationallicence oral drug delivery nationallicence peptide absorption nationallicence intestinal perfusion nationallicence intestinal metabolism nationallicence protease inhibitors nationallicence Krondahl Eva Department of Pharmacy, University of Uppsala, Box 580, BMC SE-751 23, Uppsala, Sweden aut Orzechowski Achim Department of Drug Metabolism, Astra Pain Control AB, SE-151 85 cSödertälje, Sweden aut Ekström Gunilla Department of Drug Metabolism, Astra Pain Control AB, SE-151 85 cSödertälje, Sweden aut Lennernäs Hans Department of Pharmacy, University of Uppsala, Box 580, BMC SE-751 23, Uppsala, Sweden aut Pharmaceutical Research Kluwer Academic Publishers-Plenum Publishers 14/12(1997-12-01), 1780-1785 0724-8741 14:12<1780 1997 14 11095 https://doi.org/10.1023/A:1012144232666 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1023/A:1012144232666 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Krondahl Eva Department of Pharmacy, University of Uppsala, Box 580, BMC SE-751 23, Uppsala, Sweden aut NATIONALLICENCE 700 1- Orzechowski Achim Department of Drug Metabolism, Astra Pain Control AB, SE-151 85 cSödertälje, Sweden aut NATIONALLICENCE 700 1- Ekström Gunilla Department of Drug Metabolism, Astra Pain Control AB, SE-151 85 cSödertälje, Sweden aut NATIONALLICENCE 700 1- Lennernäs Hans Department of Pharmacy, University of Uppsala, Box 580, BMC SE-751 23, Uppsala, Sweden aut NATIONALLICENCE 773 0- Pharmaceutical Research Kluwer Academic Publishers-Plenum Publishers 14/12(1997-12-01), 1780-1785 0724-8741 14:12<1780 1997 14 11095 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer