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Effect of experimental hypoalbuminemia on the plasma protein binding of tolmetin.

机译:实验性低白蛋白血症对托美汀血浆蛋白结合的影响。

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The purpose of this work was to study tolmetin plasma protein binding in an experimental model of hypoalbuminemia in the rat. Hypoalbuminemia was produced by repetitive plasmapheresis, achieving a 26.2 +/- 4.6% reduction in albumin circulating levels. Rats then received a 100 mg/kg oral tolmetin dose. Control rats received oral tolmetin 10, 56 or 100 mg/kg. Tolmetin plasma protein binding was determined by an ultrafiltration technique using an in vivo pharmacokinetic approach. Plasma protein binding data for the 3 doses studies in control animals could be described considering a single binding site with Kd = 21.9 +/- 2.1 microM and N = 0.98 +/- 0.05 sites per molecule of albumin. For hypoalbuminemic rats Kd was significantly increased (p < 0.05), while there was no significant change in the number of binding site per albumin molecule (Kd = 131.6 +/- 38.1 microM and N = 1.58 +/- 0.77). Our results show that hypoalbuminemia produces a disproportionate increase in the free fraction of tolmetin, not only by reducing albumin concentration, but also by a decrease in affinity. The mechanism responsible of such changes in affinity remains to be elucidated.
机译:这项工作的目的是研究大鼠低白蛋白血症实验模型中托美汀血浆蛋白的结合。低血白蛋白血症是由重复性血浆置换产生的,白蛋白循环水平降低了26.2 +/- 4.6%。然后,大鼠接受100 mg / kg口服托美汀剂量。对照大鼠接受10、56或100 mg / kg的口服托美汀。使用体内药代动力学方法,通过超滤技术确定托美汀血浆蛋白的结合。考虑到每分子白蛋白Kd = 21.9 +/- 2.1 microM和N = 0.98 +/- 0.05个位点的单个结合位点,可以描述在对照动物中进行3次剂量研究的血浆蛋白结合数据。对于低白蛋白血症大鼠,Kd显着增加(p <0.05),而每个白蛋白分子的结合位点数量没有显着变化(Kd = 131.6 +/- 38.1 microM,N = 1.58 +/- 0.77)。我们的结果表明,低白蛋白血症不仅会降低白蛋白浓度,而且会降低亲和力,从而使托美汀的游离部分产生不成比例的增加。造成这种亲和力变化的机制还有待阐明。

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