Role of the kidneys in the metabolism of furosemide

Abstract

The site where furosemide is metabolized and the location where probenecid reduces furosemide metabolism remain poorly defined. The liver appears to play a minor role, and there is indirect evidence suggesting that the kidneys could be responsible for the metabolism of furosemide. To assess the role of the kidneys in the metabolism of furosemide, its intravenous kinetics have been studied in control and anephric rabbits, after the ligation of the renal pedicles. Two additional groups of rabbits, control and anephric, have received probenecid before the administration of furosemide. In the control group, the total clearance of furosemide was 18.65 +/- 1.01 mL/ min per kg; urinary and metabolic clearances of furosemide were 7.95 +/- 0.65 and 10.70 +/- 1.11 mL/min per kg, respectively. In anephric rabbits, total clearance was reduced by 85% to 2.69 +/- 0.26 mL/min per kg (P < 0.001), secondary to the abolition of furosemide renal excretion and to the reduction in metabolic clearance from 10.70 +/- 1.11 to 2.69 +/- 0.26 mL/min per kg (P < 0.001). The pretreatment with probenecid reduced the total clearance of furosemide by 80%, to 3.62 +/- 0.24 mL/min per kg (P < 0.001), because of a reduction of 90 and 75% in urinary and metabolic clearances, respectively. The administration of probenecid to anephric rabbits did not reduce further the metabolic clearance. It is concluded that the kidneys are responsible for 85% of furosemide total clearance, either via excretion (43%) or biotransformation (42%), and that probenecid inhibits both processes.

Amelioration of mercury nephrotoxicity after pharmacological manipulation of organic anion transporter 1 (Oat1) and multidrug resistance-associated protein 2 (Mrp2) with furosemide

“…The unchanged drug is the main pathway of renal elimination of furosemide but its metabolic clearance via glucuronidation is also very significant in the kidney. [42][43][44] It has been suggested that furosemide is actively transported by Mrp2. 44 Accordingly, we propose that the potential increase mechanism in Mrp2 protein expression by furosemide is via direct substrate stimulation, similar to the proposed mechanism by Kim et al 18 for the furosemide-induced up-regulation of the Oat1 protein.…”

Diuretic effect of co-administration of furosemide and albumin in comparison to furosemide therapy alone: An updated systematic review and meta-analysis

“…Pichette et al had reported that hypoalbuminemia is associated with an increase in the renal metabolic clearance of furosemide, possibly because of the increase in the concentration of unbound furosemide. This increased renal metabolic clearance of furosemide could lead to a reduction in active form furosemide tubular secretion in the S1 segments of proximal tubules [ 6 , 32 ]. Later studies further confirmed that albumin infusion in hypoalbuminemic patients does increase renal furosemide excretion [ 21 ].…”

Molecular mechanisms of loop diuretics on renal calcium and magnesium transport

“…Loop diuretics primarily exist in the circulation, bound to plasma proteins, and are mainly secreted into the luminal fluid via anion transporters in the proximal tubule. 2 From here, they move with luminal fluid to the TAL, where they bind and inhibit the NKCC2 transporter, which is responsible for the reclamation of sodium and chloride from the TAL, resulting in a significant natriuretic response. 3 In addition to salt wasting, loop diuretics further diminish the osmotic gradient in the kidney by restricting interstitial sodium chloride accumulation in the medullary interstitium, thereby limiting urinary concentrating capacity and consequently markedly increasing urine volume.…”

“…They act by inhibiting the furosemide‐sensitive NKCC2 cotransporter, encoded by the SLC12A1 gene (Figure 1). Loop diuretics primarily exist in the circulation, bound to plasma proteins, and are mainly secreted into the luminal fluid via anion transporters in the proximal tubule 2 . From here, they move with luminal fluid to the TAL, where they bind and inhibit the NKCC2 transporter, which is responsible for the reclamation of sodium and chloride from the TAL, resulting in a significant natriuretic response 3 .…”