title: Development and in vivo characterization of a novel peptide drug delivery system providing extended plasma half life.
abstract: It was the aim of this study to develop a sustained parenteral peptide (DALCE) delivery system by the immobilization of DALCE to thiolated carboxymethyl dextran-cysteine (CMD-Cys) via disulfide bond formation. The resulting CMD-Cys-DALCE conjugate displayed a 22.6±7.9% (m/m) of DALCE (mean±S.D.; n=3). The conjugation of DALCE with CMD-Cys was confirmed by FTIR-ATR spectroscopy. In vitro release studies of conjugate CMD-Cys-DALCE in the presence of 2 μM/ml reduced glutathione (GSH) being also available in the plasma showed a sustained peptide release over a time period of 8 h, because of thiol/disulfide exchange reactions. For in vivo pharmacokinetic study, DALCE and CMD-Cys-DALCE were administered intravenously to male Sprague-Dawley rats at a dose of 1mg/kg. The AUC(0-8) (ng.min/ml) was determined to be 268848±924 and 40019±495 for CMD-Cys-DALCE and DALCE, respectively. The mean residence time (MRT) was determined to be 256±8 and 53.1±9.5 min for CMD-Cys-DALCE and for DALCE, respectively. CMD-Cys-DALCE showed a more than 5-fold increased elimination half-life (p<0.01), 3-fold decreased volume of distribution (p<0.01) and a 6.7-fold decreased plasma clearance rate (p<0.01) compared to DALCE. According to these findings, CMD-Cys-DALCE seems to act as prodrug by improving half-life and decreasing plasma clearance.
authors: Department of Pharmaceutical Technology, Institute of Pharmacy, University of Innsbruck, Innrain 52c, Josef Möller Haus, 6020 Innsbruck, Austria.
authors: Gul
authors: G
authors: Shahnaz
authors: Javed
authors: J
authors: Iqbal
authors: Deni
authors: D
authors: Rahmat
authors: Glen
authors: G
authors: Perera
authors: Flavia
authors: F
authors: Laffleur
authors: Denise
authors: D
authors: Rossi
authors: Andreas
authors: A
authors: Bernkop-Schnürch
mesh_terms: D000818:Animals; D003545:Cysteine / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D003911:Dextrans / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D016503:Drug Delivery Systems; D016308:Enkephalin, Leucine-2-Alanine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics; D005978:Glutathione / Q000737:chemistry; D006207:Half-Life; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D003911:Dextrans; C053821:enkephalin-Leu, Ala(2)-Cys(6)-; D016308:Enkephalin, Leucine-2-Alanine; C014392:carboxymethyl dextran; D005978:Glutathione; D003545:Cysteine