Synthesis, IN VITRO and IN VIVO studies of Dextrin-Zidovudine Conjugate

Abstract

Zidovudine was used for treatment of acquired immunodeficiency syndrome (AIDS) caused by human immunodeficiency viruses (HIV) as a single or combination therapies. The short plasma half-life of zidovudine demands a frequent and large dose regimen for the treatment of HIV infections resulting in a high risk of toxicities. To overcome these drawbacks dextrin-zidovudine conjugate was synthesized to prolong the release of zidovudine. Zidovudine firstly reacted with succinic anhydride and the succinylated zidovudine was subsequently conjugated with dextrin. The structure of the dextrin-zidovudine conjugate was characterized by FT-IR and 1H-NMR spectroscopy. The drug loading in the dextrin-zidovudine conjugate was 18.92 percent. The in vitro releases of free zidovudine and succinylated zidovudine from the dextrin-zidovudine conjugate were investigated in buffer solutions at pH 5.5, 7.4 and in human plasma. The total released zidovudine and succinylated zidovudine from the conjugate were 1.4% at pH 5.5, 41.7% at pH 7.4 and 78.4% in human plasma after 24 h. The drug release was complete in human plasma within 48h. The study of red blood cell lysis showed that the dextrin-zidovudine conjugate exhibited low hemolytic effect. The cytotoxicity of the dextrin-zidovudine conjugate was investigated in lung epithelial cells and the result showed that the dextrin-zidovudine conjugate was less toxic than free drug. An in vivo drug release study was conducted in rats. The dextrin-zidovudine conjugate and zidovudine were administered by intravenous route. The dextrin-zidovudine conjugate showed prolonged release of zidovudine compared with free zidovudine in blood circulation. The pharmacokinetic properties of the dextrin-zidovudine conjugate such as plasma half-life were improved. The zidovudine plasma half-life of the dextrin-zidovudine conjugate was extended from 1.3 h to 19.3 h.