新型小分子靶向药物NCE大鼠在体肠吸收特性及药动学研究

Intestinal absorption characteristics and pharmacokinetics of the novel targeted small-molecular NCE in rats

目的.研究新型小分子靶向药物4-（4-（3-三氟甲基）苯甲酰胺基）苯氧基-2-（甲基胺甲酰基）吡啶4-甲基苯磺酸盐（NCE）大鼠在体肠吸收特性及药动学。方法.18只健康SD大鼠随机分为3组，将高、中、低剂量（40，20，2 μg·mL^-1）的NCE按在体单向肠灌流模型灌肠，以重量法计算NCE在大鼠肠道内的吸收特性参数。单剂量90mg·kg^-1 NCE灌胃和静脉给药，HPLC法测定血浆中药物的浓度，以DAS2.1.1软件计算NCE的主要药动学参数。结果.高浓度与低浓度相比，三肠段的Papp值和Ka值均无显著性差异；在同一浓度时，各肠段的Ka值和Papp值均无显著差异。NCE口服混悬剂的绝对生物利用度为44.18％。结论.NCE在大鼠整个小肠均有吸收，无吸收部位特异性，且在2～40 μg·mL^-1范围内，随着质量浓度的增加，其吸收有上升趋势，但Papp值和Ka值均无显著性差异，提示其在小肠的吸收机制为被动扩散；NCE口服生物利用度适中，可采用制剂学手段进一步提高其口服生物利用度。

Objective： To determine the in-situ intestinal absorption characteristics and pharmacokinetics of 2-methylcarbamoyl-4-{ 4-[3-（trifluoromethyl） benzamido 3 phenoxy t pyridinium 4-methylbenzenesulfonate monohydrate （NCE） in rats. Methods： Eighteen SD rats were randomly divided into three groups, and their intestines were perfused with NCE （2, 20 and 40 μg·mL^-1） by an in-situ rat sing/e-pass intestinal perfusion method. Gravi- metric method was used to calculate the intestinal absorption parameters. A single NCE dose of 90 mg.kg^-1 was administered to rats intragastrically and intravenously. The concentrations of NCE were determined by HPLC and the main pharmacokinetics parameters were calculated by using DAS 2.1.1 software. Results： The absorbanee of NCE was increased with the increasing of NCE concentration. The P pp values of the three segments had no significant influence between low and high concentrations. At the same NCE concentration, the KS and P pp values in different intestinal segment had no significant influence. The oral absolutely bioavailability of NCE suspension was 44.18%. Conclusion： NCE are absorbed in the whole intestinal tract without absorption selectivity in intestinal segments. The NCE absorption increases with the increasing of concentration within 2 ～ 40 μg·mL^-1, but the Papp values of the three segments have no significant influence between low and high concentrations, indicating passive diffusion is the major mechanism of NCE absorption. The oral bioavailability of NCE is temperate, indicating that its oral bioavailability can be imoroved by pharmaceutical formulation.