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 (IV) 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 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 significantly (48·2 versus 43·0 μg) and the amount of M1 formed increased significantly (4.88 versus 6.66 μg when expressed in terms of azosemide) in 3‐MC pretreated rats after 30 min incubation of 50 μg 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. © 1997 John Wiley & Sons, Ltd.

Pharmacokinetics of drugs in rats with diabetes mellitus induced by alloxan or streptozocin: comparison with those in patients with type I diabetes mellitus

“…[114] In male Sprague-Dawley rats, azosemide was metabolized via hepatic CYP1A1/2 (not via CYP2B1/2 and 2E1). [115] After the intravenous administration of 10 mg/ kg azosemide to DMIA rats on the fourth day, the CL NR of azosemide became comparable with that of the controls. [116] This could possibly have been due to the increase in the free fractions of azosemide in the plasma of the DMIA rats (not measured), since the protein expression and mRNA level of hepatic CYP1A1, and 1A2 increased in the DMIA rats (Table 1).…”

Pharmacokinetics of Oltipraz in Mutant Nagase Analbuminemic Rats

“…Although, the changes in pharmacokinetics of many drugs in NARs were reported, the pharmacokinetic changes of drugs in NARs with respect to changes in CYP isozymes seemed not to be reported except azosemide8 and theophylline 9. The significantly faster time‐averaged nonrenal clearance ( CL NR ) of azosemide8 and theophylline9 (307% and 49.3% increase, respectively) in NARs were reported, since azosemide is mainly metabolized via CYP1A2 in rats10 and theophylline was metabolized to 1,3‐dimethyluric acid via CYP1A2 in rats 11. Hence, it could be expected that the time‐averaged total body clearance ( CL ) of oltipraz is significantly faster in NARs at least partly due to the increase in CYP1A2 in NARs 8.…”

Effects of cysteine on the pharmacokinetics of intravenous chlorzoxazone in rats with protein–calorie malnutrition

“…The following results were also obtained from our laboratories. After intravenous administration of azosemide, a loop diuretic, primarily metabolized by cytochrome CYP1A in rats [6], the time-averaged nonrenal clearance (Cl nr ) of azosemide decreased significantly in rats with PCM. Interestingly, cysteine supplementation (rats with PCMC) significantly reduced the plasma concentrations of the diuretic and concomitantly restored Cl nr toward control [5,7].…”