Influence of Protein and Calorie Malnutrition on the Pharmacokinetics and Pharmacodynamics of Bumetanide in Rats

Abstract

Bumetanide is a loop diuretic that is used for the treatment of edema and hypertension. The rapidly developing syndrome of extracellular fluid overload in some malnourished children has been successfully treated with furosemide, another loop diuretic, and digoxin; however, similar studies with bumetanide have not been conducted to date. Therefore, in the present study, the influence of dietary protein deficiency on the pharmacokinetics and pharmacodynamics of bumetanide was investigated after intravenous (iv) bolus and oral administration of bumetanide to male Sprague-Dawley rats fed on 23% (control rats) or 5% [protein and calorie malnutrition (PCM) rats] protein diet ad libitum for 4 weeks. After an iv dose of bumetanide, 1 mg/100 g body weight, the mean values of renal clearance and percentages of dose excreted as unchanged bumetanide in an 8-h urine sample were 166 and 154% higher, respectively, in PCM than control rats; however, nonrenal clearance (CLNR) was 28% lower. The decrease in nonrenal clearance in PCM rats might be because of the decrease in nonrenal metabolism of bumetanide in PCM rats. The urine output per 100 g of body weight was not significantly different between the two groups of rats after iv administration, although the amount of bumetanide excreted in the 8-h urine sample per 100 g body weight increased significantly in PCM rats. These results could be explained by the fact that the dose of bumetanide used results in urinary excretion rate of bumetanide at the plateau of the concentration-effect relationship. The amounts of sodium, potassium, and chloride excreted in the 8-h urine sample per 100 g body weight were not significantly different between the control and PCM rats after iv administration. Therefore, the diuretic, natriuretic, kaluretic, and chloru- retic efficiencies were significantly reduced in PCM rats after iv administration. After an oral dose of bumetanide at 2 mg/100 g body weight, the extent of bioavailability increased considerably from 21.3 to 36.9% in PCM rats, probably as a result of decreased hepatic first-pass metabolism. The increase in bioavailability in PCM rats may be supported by the results of liver homogenate study; the amount of bumetanide remaining per gram of liver after 30 min of incubation of 100 /μg of bumetanide with the 9000 x g supernatant fraction of the liver homogenate increased significantly (85.5 versus 102 /μg) in PCM rats. The 8-h urine output, and amounts of sodium, potassium, and chloride excreted in the 8-h urine sample per 100 g body weight increased significantly in PCM rats after oral administration as a result of significantly increased amounts of bumetanide excreted in the 8-h urine sample. However, the diuretic, natriuretic, kaluretic, and chloruretic efficiencies were significantly reduced in PCM rats.