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

2001

Biopharm & Drug Disp

Self Cite

The importance of plasma protein binding of intravenous furosemide in circulating blood for its urinary excretion and hence its diuretic effects in mutant Nagase analbuminemic rats was reported. Based on the furosemide report, the diuretic effects of another loop diuretic, bumetanide, could be expected in analbuminemic rats if plasma protein binding of bumetanide is considerable in the rats. This was proved by this study. After intravenous administration of bumetanide, 10 mg/kg, to analbuminemic rats, the plasma protein binding of bumetanide was 36.8% in the rats mainly due to considerable binding to alpha- and beta-globulins (this value, 36.8%, was considerably greater than only 12% for furosemide), and hence the percentages of intravenous dose of bumetanide excreted in 6 h urine as unchanged drug was 16.0% in the rat (this value was considerably greater than only 7% for furosemide). After intravenous administration of bumetanide to analbuminemic rats, the area under the plasma concentration-time curve from time zero to time infinity (1012 compared with 2472 microg min/mL) was significantly smaller [due to significantly faster both renal clearance (1.49 compared with 0.275 ml/min/kg) and nonrenal clearance (8.30 compared with 3.71 ml/min/kg)], terminal half-life (9.94 compared with 22.4 min) and mean residence time (4.25 compared with 5.90 min) were significantly shorter (due to faster total body clearance, 9.88 compared with 4.05 ml/min/kg), and amount of 6 h urinary excretion of unchanged bumetanide (559 compared with 261 microg, due to increase in intrinsic renal excretion) was significantly greater than that in control rats. The 6 h urine output and 6 h urinary excretions of sodium, chloride and potassium were comparable between two groups of rats although the 6 h urinary excretion of bumetanide was significantly greater in analbuminemic rats. This could be explained by the following. The amount of urinary excretion of bumetanide was significantly greater in analbuminemic rats than that in control rats only between 0 and 30 min urine collection. In both groups of rats, the urinary excretion rates of bumetanide during 0-30 min reached a upper plateau with respect to urine flow rate as well urinary excretion rates of sodium, potassium and chloride, therefore, the diuretic effects (6 h urine output and 6 h urinary excretions of sodium, potassium and chloride) were not significantly different between two groups of rats.

Section: Discussionsupporting

confidence: 88%

Section: Discussionmentioning

confidence: 99%

Section: Intravenous Studymentioning

confidence: 99%

Section: Intravenous Studymentioning

confidence: 99%

Section: Intravenous Studymentioning

confidence: 99%

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Pharmacokinetics and pharmacodynamics of intravenous bumetanide in mutant nagase analbuminemic rats: importance of globulin binding for the pharmacodynamic effects

Kim

2001

Biopharm & Drug Disp

Self Cite

Effect of Phenobarbital, 3-Methylcholanthrene, and Chloramphenicol Pretreatment on the Pharmacokinetics and Pharmacodynamics of Azosemide in Rats

1997

Biopharm. Drug Dispos.

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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.

Pharmacokinetic changes of M1, M2, M3 and M4 after intravenous administration of a new anthracycline, DA-125, to rats pretreated with phenobarbital, 3-methylcholanthrene, chloramphenicol, or SKF-525A

Choi

Kwon

et al. 1998

Biopharm. Drug Dispos.

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The pharmacokinetics of M1–M4, the metabolites of a new anthracycline antineoplastic agent, DA‐125, were compared after intravenous (IV) administration of DA‐125, 15 mg kg−1, to rats pretreated with enzyme inducers, such as phenobarbital (PBT, n = 14) and 3‐methylcholanthrene (MCT, n = 15), or enzyme inhibitors, such as SKF‐525A (SKT, n = 11) and chloramphenicol (CMT, n = 15), and to their control rats (n = 15 for PBC, CMC or SKC, and n = 11 for MCC). After IV administration of DA‐125, the plasma concentrations of both M1 and M2 declined slowly from 1 to 2 h onwards to 8 h in all groups of rats due to the continuous formation of M2 from M1. The AUC0–8 h of M1 (47.1 versus 7.85 μg min mL−1) and M2 (20.7 versus 44.3 μg min mL−1) decreased significantly in the PBT group compared to those in the PBC group. However, the corresponding value of only M1 (74.6 versus 89.9 μg min mL−1) decreased significantly in the MCT group. The above data indicate that metabolism of M1 is increased by pretreatment with both PB and 3‐MC, and that of M2 with PB, but not with 3‐MC. The AUC0–8 h of both M1 (126 versus 78.5 μg min mL−1) and M2 (69.2 versus 44.3 μg min mL−1) increased significantly in the SKT group compared to the SKC group. However, the corresponding values were not significantly different between CMC and CMT groups. The above data indicate that the metabolism of both M1 and M2 is inhibited by pretreatment with SKF‐525A, but not with CM. © 1998 John Wiley & Sons, Ltd.