Lee S H, Lee M G
College of Pharmacy, Seoul National University, Korea.
Biopharm Drug Dispos. 1997 Jul;18(5):371-86. doi: 10.1002/(sici)1099-081x(199707)18:5<371::aid-bdd40>3.0.co;2-l.
The effects of pretreatment with the enzyme inducers phenobarbital (PB) and 3-methylcholanthrene (3-MC) and the enzyme inhibitor chloramphenicol (CM) on the pharmacokinetic and pharmacodynamic parameters of azosemide were examined after intravenous (i.v.) administration of azosemide, 10 mg kg-1, to rats. The nonrenal clearance (1.63 versus 3.30 mL min-1 kg-1) of azosemide increased significantly in 3-MC pretreated rats. This suggested that the nonrenal metabolism of azosemide increased by pretreatment with 3-MC. This relationship was supported by the significant decrease in 24 h urinary excretion of unchanged azosemide in 3-MC pretreated rats (54.1 versus 41.1% of i.v. dose). This relationship was also supported at least in part by the results of a liver homogenate study; the amount of azosemide remaining per gram of liver decreased significantly (48.2 versus 43.0 micrograms) and the amount of M1 formed increased significantly (4.88 versus 6.66 micrograms when expressed in terms of azosemide) in 3-MC pretreated rats after 30 min incubation of 50 micrograms azosemide in 9000 g supernatant fractions of liver homogenates. The content of hepatic cytochrome P-450 (0.751 versus 1.57 nmol/mg protein) and the weight of liver (3.53 versus 4.20% of body weight) increased significantly in 3-MC pretreated rats, suggesting that the metabolizing enzyme(s) for azosemide seemed to be induced by pretreatment with 3-MC. The 8 h urine output (29.2 versus 18.1 mL) and 8 h urinary excretion of sodium (4.02 versus 2.39 mmol) and chloride (4.01 versus 2.73 mmol) per 100 g body weight decreased significantly in 3-MC pretreated rats. However, the diuretic, natriuretic, kaluretic, and chloruretic efficiencies were not significantly different between the control and 3-MC pretreated rats. The pharmacokinetic and pharmacodynamic parameters of azosemide were not significantly different between the control and PB pretreated rats, and similar results were also obtained from the control and CM pretreated rats. The above data indicate that the metabolizing enzyme(s) for azosemide seem(s) to be neither induced by PB pretreatment nor inhibited by CM pretreatment. However, the content of hepatic cytochrome P-450 and the weight of liver increased significantly in PB pretreated rats, while the values were not significantly different between the control and CM pretreated rats.
给大鼠静脉注射10 mg/kg阿佐塞米后，研究了用酶诱导剂苯巴比妥（PB）和3-甲基胆蒽（3-MC）以及酶抑制剂氯霉素（CM）预处理对阿佐塞米药代动力学和药效学参数的影响。在3-MC预处理的大鼠中，阿佐塞米的非肾清除率（1.63对3.30 mL·min-1·kg-1）显著增加。这表明3-MC预处理增加了阿佐塞米的非肾代谢。3-MC预处理的大鼠中阿佐塞米原形24小时尿排泄量显著降低（静脉注射剂量的54.1%对41.1%），支持了这种关系。肝脏匀浆研究结果也至少部分支持了这种关系；在肝脏匀浆9000g上清液组分中孵育50μg阿佐塞米30分钟后，3-MC预处理的大鼠每克肝脏中剩余的阿佐塞米量显著降低（48.2对43.0μg），形成的M1量显著增加（以阿佐塞米计为4.88对6.66μg）。3-MC预处理的大鼠肝脏细胞色素P-450含量（0.751对1.57 nmol/mg蛋白质）和肝脏重量（占体重的3.53%对4.20%）显著增加，表明阿佐塞米的代谢酶似乎被3-MC预处理诱导。3-MC预处理的大鼠每100g体重的8小时尿量（29.2对18.1 mL）以及8小时尿钠（4.02对2.39 mmol）和尿氯（4.01对2.73 mmol）排泄量显著降低。然而，对照组和3-MC预处理大鼠之间的利尿、利钠、利钾和利氯效率没有显著差异。对照组和PB预处理大鼠之间阿佐塞米的药代动力学和药效学参数没有显著差异，对照组和CM预处理大鼠也得到了类似结果。上述数据表明，阿佐塞米的代谢酶似乎既不被PB预处理诱导，也不被CM预处理抑制。然而，PB预处理的大鼠肝脏细胞色素P-450含量和肝脏重量显著增加，而对照组和CM预处理大鼠之间这些值没有显著差异。
