文摘
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 ¡À 7.9 % (m/m) of DALCE (mean ¡À 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 ¦ÌM/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 1 mg/kg. The AUC0-8 (ng.min/ml) was determined to be 268848 ¡À 924 and 40019 ¡À 495 for CMD-Cys-DALCE and DALCE, respectively. The mean residence time (MRT) was determined to be 256 ¡À 8 and 53.1 ¡À 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.
