Pharmacokinetics and pharmacodynamics of intravenous bumetanide in mutant nagase analbuminemic rats: Importance of globulin binding for the pharmacodynamic effects
Pharmacokinetics and pharmacodynamics of intravenous bumetanide in mutant nagase analbuminemic rats: Importance of globulin binding for the pharmacodynamic effects
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DOI：
10.1002/bdd.267
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发表时间：
2001-05-01
影响因子：
2.1
通讯作者：
Lee, MG
中科院分区：
文献类型：
--
作者：
Kim, EJ;Lee, MG
本文报道了静脉注射速尿与循环血中血浆蛋白结合对尿液排泄的重要性，以及对突变NAGase类似蛋白血症大鼠的利尿作用。根据呋塞米的报告，如果布美他尼与大鼠的血浆蛋白结合相当，另一种环状利尿剂布美他尼对大鼠的利尿作用是可以预期的。这项研究证明了这一点。大鼠静脉注射布美他尼10 mg/kg后，布美他尼的血浆蛋白结合率为36.8%，主要是由于与α和β-球蛋白的结合(36.8%，明显高于速尿的12%)，因此布美他尼静脉剂量在大鼠6h尿中排泄的比例为16.0%(显著高于速尿的7%)。大鼠静脉注射布美他尼后，血药浓度-时间曲线下面积从时间0到无限远(1012vs2472mugmin/ml)[由于肾清除(1.49vs2472mlmin/kg)和非肾清除(8.30vs3.71mlmin/kg)]、终末半衰期(9.94vs22.4min)和平均停留时间(4.25vs5.90min)显著缩短(由于更快的全身清除，6h尿排泄量(肾内源性排泄量增加，分别为559和261µg)均显著高于对照组。两组大鼠的6h尿量和6h尿钠、氯、钾排泄量相似，但布美他尼的6h尿排出量明显高于对照组。这可以用以下几点来解释。大鼠尿中布美他尼排泄量仅在0~30min时显著高于对照组。在两组大鼠中，布美他尼在0~30min的尿流率和尿钠、钾、氯排泄率均达到平台期，因此两组大鼠的利尿效果(6h尿量和6h尿钠、钾、氯排泄量)无显著差异。版权所有(C)2001 John Wiley&Sons，Ltd.
The importance of plasma protein binding of intravenous furosemide in circulating blood for its urinary excretion and hence its diuretic effects in mutant Nagase analbuminemic rats was reported. Based on the furosemide report, the diuretic effects of another loop diuretic, bumetanide, could be expected in analbuminemic rats if plasma protein binding of bumetanide is considerable in the rats. This was proved by this study. After intravenous administration of bumetanide, 10 mg/kg, to analbuminemic rats, the plasma protein binding of bumetanide was 36.8% in the rats mainly due to considerable binding to alpha- and beta -globulins (this value, 36.8%, was considerably greater than only 12% for furosemide), and hence the percentages of intravenous dose of bumetanide excreted in 6 h urine as unchanged drug was 16.0% in the rat (this value was considerably greater than only 7% for furosemide). After intravenous administration of bumetanide to analbuminemic rats, the area under the plasma concentration-time curve from time zero to time infinity (1012 compared with 2472 mug min/mL) was significantly smaller [due to significantly faster both renal clearance (1.49 compared with 0.275 ml/min/kg) and nonrenal clearance (8.30 compared with 3.71 ml/min/kg)], terminal half-life (9.94 compared with 22.4 min) and mean residence time (4.25 compared with 5.90 min) were significantly shorter (due to faster total body clearance, 9.88 compared with 4.05 ml/min/kg), and amount of 6 h urinary excretion of unchanged bumetanide (559 compared with 261 mug, due to increase in intrinsic renal excretion) was significantly greater than that in control rats. The 6 h urine output and 6 h urinary excretions of sodium, chloride and potassium were comparable between two groups of rats although the 6 h urinary excretion of bumetanide was significantly greater in analbuminemic rats. This could be explained by the following. The amount of urinary excretion of bumetanide was significantly greater in analbuminemic rats than that in control rats only between 0 and 30 min urine collection. In both groups of rats, the urinary excretion rates of bumetanide during 0-30 min reached a upper plateau with respect to urine flow rate as well urinary excretion rates of sodium, potassium and chloride, therefore, the diuretic effects (6 h urine output and 6 h urinary excretions of sodium, potassium and chloride) were not significantly different between two groups of rats. Copyright (C) 2001 John Wiley & Sons, Ltd.