The eects of pretreatment with the enzyme inducers phenobarbital (PB) and 3methylcholanthrene (3-MC) and the enzyme inhibitor chloramphenicol (CM) on the pharmacokinetic and pharmacodynamic parameters of azosemide were examined after intravenous (IV) administration of azosemide, 10 mg kg 71 , to rats. The nonrenal clearance (1´63 versus 3´30 mL min 71 kg 71 ) of azosemide increased signi®cantly 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 signi®cant decrease in 24 h urinary excretion of unchanged azosemide in 3-MC pretreated rats (54´1 versus 41´1% of IV 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 signi®cantly (48´2 versus 43´0 mg) and the amount of M1 formed increased signi®cantly (4.88 versus 6.66 mg when expressed in terms of azosemide) in 3-MC pretreated rats after 30 min incubation of 50 mg 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 signi®cantly 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 signi®cantly in 3-MC pretreated rats. However, the diuretic, natriuretic, kaluretic, and chloruretic eciencies were not signi®cantly dierent between the control and 3-MC pretreated rats. The pharmacokinetic and pharmacodynamic parameters of azosemide were not signi®cantly dierent 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 signi®cantly in PB pretreated rats, while the values were not signi®cantly dierent between the control and CM pretreated rats.