PHARMACOKINETICS AND PHARMACODYNAMICS OF FUROSEMIDE IN PROTEIN-CALORIE MALNUTRITION

The influence of dietary protein deficiency on pharmacokinetics and pharmacodynamics of furosemide was investigated after iv bolus (1 mg/100 g) and oral (2 mg/100 g) administration of furosemide to male Sprague Dawley rats fed on a 23% (control) or a 5% (protein calorie malnutrition: PCM) protein diet ad lib. for 4 weeks. After iv administration, the mean values of CL(R), V(SS), and the percentages of dose excreted in 8-hr urine as furosemide were increased 81, 31, and 61%, respectively, in PCM rats when compared with those in control rats, however, CL(NR) was 54% decreased in PCM rats. The decreased CL(NR) in PCM rats suggested the significantly decreased nonrenal metabolism of furosemide. The urine volume per g kidney after iv administration was not significantly different between the two groups of rats although the amount of furosemide excreted in 8-hr urine per g kidney increased significantly in PCM rats. The diuretic, natriuretic, kaluretic, and chloruretic efficiencies reduced significantly in PCM rats after iv administration. After oral administration, the extent of bioavailability increased considerably from 27.6% in control rats to 47.0% in PCM rats, probably as a result of decreased gastrointestinal and hepatic first-pass metabolism. This was supported by a tissue homogenate study; the amount of furosemide remaining per g tissue after 30-min incubation of 50 mg of furosemide with the 9000 x g supernatant fraction of stomach (42.4 vs. 47.9 mug) and liver (41.4 vs. 45.9 mug) homogenates increased significantly in PCM rats. No significant differences in CL(R) and t1/2 were found between the control and the PCM rats after oral administration. The 24-hr urine volume and the amount of sodium excreted in 24-hr urine per g kidney increased significantly in PCM rats, and this might be due to a significantly increased amount of furosemide reaching the kidney excreted in urine per g kidney.