结肠靶向吲哚美辛前药的体内外释药特性

目的 观察酶解型吲哚美辛-直链淀粉酯系列(IDM-Am-1～6)的体内外释药特性.方法 IDM-Am-1～6体外胃肠道模拟释药(胃液4 h,pH 1.2;小肠液6 h,1%猪胰酶,pH 6.8;结肠内容36 h,pH7.2),紫外分光光度计检测释放度;SD大鼠按IDM 3 mg/kg分别予IDM(原药组)与IDM-Am-3(前药组)灌胃后,于不同时间点同时取门静脉与外周血,高效液相色谱法检测血药浓度,房室法计算药动学参数.结果 IDM-Am-3在模拟胃4 h、小肠6 h、结肠36 h释药率分别为1.3%、9.3%、95.3%;前药组较原药组吸收明显滞后,门静脉血T_(max)(11.35±2.45)h、MRT(22.27±0.52)h及t_(1/2)(16.74±4.04)h显著延长,C_(max)(9.69±2.40)mg/L及AUC_(0-t)(236.7±13.1)mg/L×h明显降低,外周血AUC_(0-t)(142.8±5.9)mg/L×h较其自身门静脉血低(P<0.01).结论 IDM-Am-3有结肠靶向性能,具有门静脉缓释药动学特点.

In vitro and in vivo release properties of colon-specific prodrug of indomethacin

Objective To explore in vitro and in vivo release properties of indomethacin-block-amyloses (IDM-Am-I-6) microbially triggered. Methods In vitro dissolution of IDM-Am-1-6 was employed under simulated gastric (pH 1.2, 4 h), small intestinal (pH 6.8, 1% porcine pancreatin, 6 h), and colonic conditions (pH 7.2, faecal bacteria, 36 h), and accumulative release was determined by ultraviolet spectrophotometer. Sprague-Dawley rats were orally administered with IDM (3 mg/kg) and IDM-Am-3 respectively. IDM concentrations in peripheral blood and portal vein were determined by HPLC, and then pharmacokinetic parameters were calculated with compartment model. Results IDM-Am-3 was degraded 1.3%, 9.3% and 95.3% respectively in simulated gastric fluid for 4 h, small intestine for 6 h, and colon for 36 h, respectively. In vivo experiment of IDM-Am-3 showed that absorption was delayed obviously (P < 0.01), peak time (11.35±2.45) h, ehmination half-life (16.74±4.04) h and mean residence time (22.27 ± 0. 52) h were significantly prolonged (P < 0.01 ), as well as peak serum concentrations (9.69 ± 2.40) mg/L and AUC_(0-t) (236.7 ± 13.1 ) mg/L × h were decreased markedly (P < 0.01 ) as com-pared with those of IDM regarding to portal vein. Also, AUC_(0-t) of IDM-Am-3 in peripheral blood was re-markably lower than that in portal vein (P <0. 01 ). Conclusion IDM-Am-3 could target IDM specifically to colon and simultaneously possessed advantage of sustained release in portal vein.