Effects of phenobarbital and 3‐methylcholanthrene pretreatment on the pharmacokinetics and the pharmacodynamics of bumetanide in rats

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Abstract
The effects of pretreatment with the enzyme inducers, phenobarbital (PB) and 3‐methyl‐cholanthrene (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 μg 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 100g 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.