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.