The Renal Transport of Nitrofurantoin

Abstract

The mechanism of excretion of nitrofurantoin in the kidney was studied in anesthetized dogs by direct collection of urine from ureteral catheters. The method of stop flow analysis, involving a period of occlusion of the ureter, was applied in order to determine in which part of the nephron nitrofurantoin is excreted; in addition, simultaneous nitrofurantoin and creatinine clearance determinations were performed on four dogs at varying levels of urinary pH and plasma CO2 combining power. The results showed that nitrofurantoin is handled by glomerular filtration and tubular reabsorption. Tubular reabsorption was greater when the urine was acid. Alkalinizing the urine resulted in higher nitrofurantoin concentrations in the urine and less tubular reabsorption. TVTITROFUBANTOIN has been employed for the 1* treatment of urinary infections with increas¬ ing frequency, owing to its proved effectiveness against the majority of common urinary patho¬ gens x and the paucity of serious side reactions which it has occasioned.When nitrofurantoin (Furadantin) is given orally in appropriate dosage, clinically significant blood levels cannot be obtained; yet up to 50% of the ingested dose may be recovered from the urine in a 6 to 8 hour period.2 Previous studies of the uri¬ nary excretion of nitrofurantoin revealed a marked variability of excretion rate and concentration of the drug in different individuals and in the same individual at different periods of time.3 These find¬ ings coupled with periodic discrepancies between in vitro sensitivities to the medicament and its clin¬ ical effectiveness prompted us to study the mecha¬ nisms involved in the renal transport of nitro¬ furantoin by means of the technique of stop flow analysis 4 and clearance studies.Since nitrofurantoin is a weak acid with a pKa of 7.2, it is more dissociated in alkaline than in acid solution. The undissociated form of weak acids are able passively to penetrate the cell membrane, while the dissociated ions are unable to cross the lipid barrier.5 This weak acid property could per¬ haps explain the variability in the clinical results noted in the treatment of pyelonephritis with nitro¬ furantoin.6 Theoretically, greater renal tissue con¬ centration of nitrofurantoin would occur in an acid urine. The increase in hydrogen ions would by the law of mass action drive more of the nitrofurantoin into the undissociated form, allowing greater move¬ ment of the nitrofurantoin into the tubular cells from the urine. Alkalinization of the urine would result in a higher urine nitrofurantoin concentra¬ tion since a greater portion would be in the nonpenetrating dissociated form.The purpose of this study was twofold; first to determine the site within the nephron governing the urinary excretion of nitrofurantoin, and second the response of this mechanism to changes in uri¬ nary and plasma pH.Stop flow analysis offers a precise method where¬ by the location of the tubular site of secretion or reabsorption can be determined and graphically displayed. This technique was utilized...

Development of a Physiologically Based Pharmacokinetic Model for Nitrofurantoin in Rabbits, Rats, and Humans

“…The mechanisms leading to DILI are not completely clear, and severe fatalities due to hepatic toxicity have been reported for NFT. Animal PK studies have indicated that NFT kinetics are not linearly proportional to the administered dose [ 12 , 17 , 19 ]. At the same time, human PK exhibits high variability [ 2 , 29 , 34 ].…”

“…A study has shown that a minimum of 30% of the administered dose needs to reach the urinary bladder to obtain an optimal therapeutic effect. Animal studies have shown that the pharmacokinetics of NFT exhibits dose-dependent and non-linear kinetics, especially in the urine [ 17 , 18 , 19 ]. Additionally, human studies have shown that urine PK and plasma PK are highly variable between subjects [ 4 ].…”

Renal Excretion of Drugs and Other Xenobiotics

“…although comparable cotransporters are found in various tissues [90], Amiloride is secreted by the proximal tubule [ 12] to reach concentrations which will be high enough to inhibit the apical sodium channel only in the distal nephron. The selec tive urinary anti-infectious effect of nitrofu rantoin [150] occurs by the same mechanism. The selective renal tissue removal of heavy metals by the organic anion complexing agent 2, 3-dimercapto-l-propanesulfonate may be explained by its selective concentration in the nephron after secretion through the organic anion system [132], Luminal presence is nec essary for action of uricosuric drugs like pro benecid and sulfinpyrazone [40].…”

“…(3) Renal excretion depending on filtra tion and active secretion, with little reabsorplion: this is seen for numerous substances, like the anions p-aminohippurate [18], and the cations tetraethylammonium [104], N 1-methylnicotinamide [109], cimetidine [81,103], and mepiperphenidol [17], (4) Renal excretion depending on filtra tion and passive reabsorption, with no secre tory movement: this is the case for paraceta mol [34], and phénobarbital [142], (5) Renal excretion involving filtration, active secretion and passive reabsorption: this would be the pattern of excretion of the cations methadone [7] and quinine [ 135], and for the anions phenybutazone [47], and nitro furantoin [150]. The case of salicylate is not clear, since active reabsorption has been pos tulated to explain part of its rcabsorptive movement [106], (6) Renal excretion after filtration, active secretion, and passive and active reabsorp tion: pyrazinoatc [40,94], w-hydroxybenzoate [77], ascorbate [76], and pantothenate [68] follow this pattern of excretion.…”

Site of Action of Nitrofurantoin in Experimental Urinary Tract Infection

“…Even though nitrofurantoin does not produce effective blood levels after therapeutic doses (7), the assumption that this drug posesses antibacterial activity in kidney tissue could be based on the following observations. (i) Stop-flow data indicate that this agent is reabsorbed in the distal tubule and possibly in the adjacent portion of the proximal tubule (1).…”