caa a22 4500 477128270 CHVBK 20180405111656.0 cr unu---uuuuu 170330e19970201xx s 000 0 eng 10.1023/A:1012096510125 doi (NATIONALLICENCE)springer-10.1023/A:1012096510125 Development and in Vitro Evaluation of Systems to Protect Peptide Drugs from Aminopeptidase N [Elektronische Daten] [Andreas Bernkop-Schnürch, Michaela Marschütz] Purpose. Develop and evaluate systems to prevent aminopeptidase N caused enzymatic degradation of perorally administrated peptide drugs. Methods. Bacitracin was covalently bound to the unabsorbable carrier matrix poly(acrylic acid) (paa) in order to avoid any dilution effects of the inhibitor in the intestine as well as systemic toxic side effects. The inhibitory effect of this conjugate, of neutralized paa and N-acetylcysteine was evaluated using a brush border membrane model. Results. Whereas within 6 h of incubation 65.3 ± 3.7 μmol/1 of the substrate (L-leucine p-nitroanilide) was hydrolyzed under our assay conditions, this metabolism was reduced to 44.5 ± 6.3 μmol/1 and 49.0 ± 8.8 μmol/1 (n = 3−5; ± S.D.) using 1.5% bacitracin-polymer conjugate and 0.5% N-acetylcysteine, respectively. The same amount of bacitracin as immobilized to the polymer exhibited a comparably weaker inhibitory effect. Neutralized paa did not inhibit membrane bound aminopeptidase N. Covering the membrane with a thin mucus layer led to a significantly lowered inhibitory effect of all tested agents. Conclusions. The immobilization of enzyme inhibitors to a carrier matrix and the use of N-acetylcysteine as a novel inhibitor are promising strategies in order to overcome the enzymatic barrier caused by membrane bound peptidases. However the use of effective mucolytic agents seems to be a prerequisite. Plenum Publishing Corporation, 1997 inhibition of aminopeptidase N nationallicence poly(acrylic acid) nationallicence bacitracin nationallicence N-acetylcysteine nationallicence Bernkop-Schnürch Andreas aut Marschütz Michaela aut Pharmaceutical Research Kluwer Academic Publishers-Plenum Publishers 14/2(1997-02-01), 181-185 0724-8741 14:2<181 1997 14 11095 https://doi.org/10.1023/A:1012096510125 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1023/A:1012096510125 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Bernkop-Schnürch Andreas aut NATIONALLICENCE 700 1- Marschütz Michaela aut NATIONALLICENCE 773 0- Pharmaceutical Research Kluwer Academic Publishers-Plenum Publishers 14/2(1997-02-01), 181-185 0724-8741 14:2<181 1997 14 11095 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer