EFFECTS OF PHENOBARBITAL AND 3-METHYLCHOLANTHRENE PRETREATMENT ON THE PHARMACOKINETICS AND THE PHARMACODYNAMICS OF BUMETANIDE IN RATS
EFFECTS OF PHENOBARBITAL AND 3-METHYLCHOLANTHRENE PRETREATMENT ON THE PHARMACOKINETICS AND THE PHARMACODYNAMICS OF BUMETANIDE IN RATS
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DOI：
10.1002/bdd.2510120408
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发表时间：
1991-05-01
影响因子：
2.1
通讯作者：
LEE, MG
中科院分区：
文献类型：
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作者：
CHOI, YM;LEE, SH;LEE, MG
在大鼠中检查了酶诱导剂苯巴比妥 (PB) 和 3-甲基胆蒽 (3-MC) 预处理对布美他尼药代动力学和药效学参数的影响。 在 PB 治疗的大鼠中，布美他尼的非肾清除率（19.3 vs 29.6 ml min-1/kg）显着增加。 这表明布美他尼的非肾代谢通过PB预处理而增加，这通过8小时尿液中排泄的布美他尼葡萄糖醛酸和去丁基布美他尼的量显着增加以及在将100μg布美他尼与肝、胃和肾组织匀浆的9000xg上清液部分孵育30分钟后每克组织中剩余的布美他尼量减少来支持。 PB 处理大鼠。 PB处理的大鼠肝细胞色素P-450含量（1.29 vs 2.15 nmol mg-1蛋白）以及肝脏和胃的重量显着增加，表明布美他尼的代谢酶是由PB预处理诱导的。 尽管PB处理的大鼠8小时尿液中布美他尼的排泄量显着增加，但PB预处理后每100克体重的8小时尿量没有显着差异。 这可以通过以下事实来解释：布美他尼的使用剂量导致尿浓度处于浓度-效应关系的平台期。 因此，用PB预处理改变布美他尼的尿排泄率不会改变利尿作用。 在3-MC处理的大鼠中，药代动力学和药效学参数没有显着差异，这表明3-MC预处理不会诱导布美他尼的代谢酶，尽管3-MC预处理后肝细胞色素P-450的含量以及肝脏和胃的重量显着增加。
The effects of pretreatment with the enzyme inducers, phenobarbital (PB) and 3-methylcholanthrene (3-MC), on the pharmacokinetic and pharmacodynamic parameters of bumetanide were examined in rats. The nonrenal clearance (19.3 vs 29.6 ml min-1 per kg) of bumetanide increased significantly in PB treated rats. This suggested that the nonrenal metabolism of bumetanide is increased by pretreatment with PB, which was supported by significantly increased amounts of bumetanide glucuronide and desbutyl bumetanide excreted in 8-h urine, and reduced amounts of bumetanide remaining per gram of tissue after 30-min incubation of 100-mu-g of bumetanide with the 9000 xg supernatant fraction of liver, stomach, and kidney tissue homogenates in PB treated rats. The contents of hepatic cytochrome P-450 (1.29 vs 2.15 nmol mg-1 protein) and the weights of liver and stomach increased significantly in PB treated rats, suggesting that the metabolizing enzymes for bumetanide are induced by pretreatment with PB. The 8-h urine output per 100 g body weight was not significantly different by pretreatment with PB although the amounts of bumetanide excreted in 8-h urine increased significantly in PB treated rats. It could be explained by the fact that the dose of bumetanide used results in urinary concentrations at the plateau of the concentration-effect relationship. Therefore, the alteration in the urinary excretion rate of bumetanide by pretreatment with PB would not alter the diuretic effect. In 3-MC treated rats, pharmacokinetic and pharmacodynamic parameters were not significantly different and it suggested that the metabolizing enzymes for bumetanide are not induced by pretreatment with 3-MC although the contents of hepatic cytochrome P-450 and the weights of liver and stomach increased significantly by pretreatment with 3-MC.