Furosemide—108------------------------------, metabolites

The loop diuretics are rapidly absorbed. They are eliminated by the kidney by glomerular filtration and tubular secretion. Absorption of oral torsemide is more rapid (1 hour) than that of furosemide (2-3 hours) and is nearly as complete as with intravenous administration. The duration of effect for furosemide is usually 2-3 hours and that of torsemide is 4-6 hours. Half-life depends on renal function. Since loop agents act on the luminal side of the tubule, their diuretic activity correlates with their secretion by the proximal tubule. Reduction in the secretion of loop diuretics may result from simultaneous administration of agents such as NSAIDs or probenecid, which compete for weak acid secretion in the proximal tubule. Metabolites of ethacrynic acid and furosemide have been identified, but it is not known if they have any diuretic activity. Torsemide has at least one active metabolite with a half-life considerably longer than that of the parent compound. 

Following oral administration of radiolabeled furosemide, excretion was reported to be almost complete within 3 days in rats (96-98%) and dogs (98-99%). Rat urine contained 40-50% of the parent drug, 30% 4-chloro-5-sulfamoyl-anthranilic acid, and four unidentified metabolites that accounted for the rest of the administered radioactivity. In contrast, urine of dog and monkey contained 85% unmetabolized furosemide, 7% 4-chloro-5-sulfamoyl-anthranilic acid, and the remainder was due to unidentified metabolites. Following intramuscular injection of 5 mg furosemide/kg bw in cattle, the half-life for plasma elimination was estimated at 4.3 h. In contrast, the half-life of furosemide in cattle was reported to be less than 1 h following intravenous administration. 

Other compounds cause liver necrosis because of biliary excretion. Thus, the drug furosemide causes a dose-dependent centrilobular necrosis in mice. The liver is a target as a result of its capacity for metabolic activation and because furosemide is excreted into the bile by an active process, which is saturated after high doses. The liver concentration of furosemide therefore rises disproportionately (chap. 3, Fig. 34), and metabolic activation allows the production of a toxic metabolite (Fig. 6.6). The drug proxicromil (chap. 5, Fig. 11) caused hepatic damage in dogs as a result of saturation of biliary excretion and a consequent increase in hepatic exposure. 

Ultrafiltration has been used to determine the protein bound fraction of many drags, such as methadone (Wilkins et al. 1997), phenylacetate and phenylbu-tyrate (Boudoulas et al. 1996), etoposide (Robieux et al. 1997), doxorubicin and vincristine (Mayer and St-Onge 1995), disopyramide (Echize et al. 1995), and ketamine and its active metabolites (Hijazi and Boulieu 2002). Schumacher et al. (2000) have shown the applicability for the determination of erythro-cyte/plasma distribution. The method of UF has been applied in the measurement of free unaltered thyroxin or after displacement by salicylate as well after displacement by heparin in healthy people and in patients with non-thyroidal somatic illness (Faber et al. 1993). The protein binding of tritium labeled, antidiabetic repaglinide and its displacement by warfarin, furosemide, tolbutamide, diazepam, glibenclamide and nicardipine were determined by ultrafiltration (Plumetal. 2000). 

Mitchell JR, Nelson WL, Potter WZ, Sasame HA, Jollow DJ. Metabolic activation of furosemide to a chemically reactive, hepatotoxic metabolite. J Pharmacol Exp Ther 1976 199 41-52. 

The binding of drug to tissue is usually reversible. In some cases, however, there is covalent binding, which by definition is not reversible. This applies to drug or metabolite and could be important because it could be related to toxicity. " A good correlation has been reported in animals between the degree of covalent binding to hepatic protein and the severity of hepatic necrosis of paracetamol, isoniazid, adriamycin, and furosemide. " ... 

The concentration of the active metabolite mesoridazine falls more markedly. Phenytoin and phenobarbital reduce furosemide absorption. 

Figure 18-13 Various seemingly unrelated agents that block Na reabsorption in the thick ascending limb of Henle s loop, The precise mechanism of action of muzolimine is unknown. All of the other agents are inactive as such and must be biotransformed to active metabolites before their diuretic activity can be expressed. In each case, like furosemide, bumetanide, torsemide, and ethacrynic acid, the active metabolites have an anionic moiety that may permit binding to the Cl -binding site on the 1Na /1K /2CI cotransport system in thick ascending limb cells.

Carretero, I. Vadillo, J.M. Laserna, J.J. Determination of antipyrine metabolites in human plasma by solid-phase extraction and micellar liquid chromatography. Analyst, 1995,120, 1729-1732 [plasma SPE furosemide is IS]... 

Campfns-Falco, R Herraez-Herndndez, R. Sevillano-Cabeza, A. Solid-phase extraction techniques for assay of diuretics in human urine samples. J.Liq.Chromatogr., 1991, 14, 3575-3590 [SPE hydrox-yethyltheophylline (IS) extracted acetazolamide, amiloride, bendroflumethiazide, bumetanide, chlorthalidone, ciclothiazide, ethacrynic acid, furosemide, hydrochlorothiazide, probenecid, spironolactone] Shah, V.R Walker, M.A. Prasad, V.K. Application of flow programming in the analysis of drugs and their metabolites in biological fluids. J.Liq.Chromatogr., 1983, 6, 1949-1954 [urine plasma also chlorothiazide, hydrochlorothiazide]... 

Fig. 3 Bioactivation of model hepatotoxins. The stractures of the toxic metabolites that are formed from oxidative metabolism of acetaminophen, bromobenzene, carbon tetrachloride, and furosemide are given alongside the requirement for GSH depletion and covalent binding...

Williams GM, latropoulos MJ, Djordjevic MV et al (1993) The triphenylethylaie dmg tamoxifen is a strong liver carcinogen in the rat. Carcinogenesis 14 315—317 Williams DP, Kitteringham NR, Naisbitt DJ et al (2002) Are chemically reactive metabolites responsible for adverse reactions to drags Curr Drag Metab 3 351-366 Williams DP, Antoine DJ, Butler PJ et al (2007) The metabolism and toxicity of furosemide in the Wistar rat and CD-I mouse a chemical and biochemical definition of the toxicophore. J Pharmacol Exp Ther 322 1208-1220... 

Wong SG, Card JW, Racz WJ (2000) The role of mitochondrial injury in bromobenzene and furosemide induced hepatotoxicity. Toxicol Lett 116 171-181 Yukinaga H, Takami T, Shioyama SH et al (2007) Identification of cytochrome P450 3A4 modification site with reactive metabolite using linear ion trap-Fourier transform mass spectrometry. Chem Res Toxicol 20 1373-1378... 

Not understood. One suggestion is that furosemide displaces trichloroacetic acid (the metabolite of cloral hydrate) from its protein binding sites, which in its turn displaces levothyroxine or alters the serum pH so that the levels of free levothyroxine rise leading to a hypermetabolic state. ... 

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