Effect of phenobarbital, 3-methylcholanthrene, and chloramphenicol pretreatment on the pharmacokinetics and pharmacodynamics of azosemide in rats.

Abstract

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.