Nitrofurantoin (0-512 mg/L; 8 hours) treatment stops E. coli from growing. isolates of E. Coli [3].

1.19 Nitrofurantoin's pharmacokinetic effects in SD rats [4]. Measurement AUC0-720 (μg/mL·min) at 10 mg/kg po and 2 mg/kg iv AUC0-120 (μg/mL·min) = 306 90.3 (μg/mL·min) AUC0-∞ 344 Cmax (μg/mL) = 91.5 CL/F or CL (ml/min/kg) = 1.01 31.0 22.7 seconds (t1/2) Bioavailability (%) 166 23.6 60.1

Cell Viability Assay[3]
Cell Types: E. coli Isolates: DA10708, DA13815, DA13824, DA13957, DA13992, DA10626, DA10627
Tested Concentrations: 0, 32, 64, 128, 256 and 512 mg/L
Incubation Duration: 8 hrs (hours)
Experimental Results: For DA10708, DA13815 and DA13824, a bactericidal effect was observed at 32 mg/L. The growth of DA13957 and DA13992 was completely inhibited at 128 mg/L, and a bactericidal effect was observed at 256 mg/L. DA10626 and DA10627 demonstrated moderate lethality at >128 mg/L.

Absorption, Distribution and Excretion
The peak plasma concentration (Cmax) of nitrofurantoin is 0.875–0.963 mg/L, and the AUC is 2.21–2.42 mg·h/L. Its bioavailability is 38.8–44.3%. Co-administration with food increases the absorption of nitrofurantoin and prolongs the duration of therapeutic concentrations in urine. 27–50% of the oral dose is excreted unchanged in the urine. 90% of the total dose is excreted in the urine. Data on the volume of distribution in humans are scarce, but it has been reported to be 0.46 L/kg in dogs. The clearance of nitrofurantoin is 16.7–19.4 L/h. It is rapidly and completely absorbed from the gastrointestinal tract. The plasma half-life is 0.3 to 1 hour; approximately 40% is excreted unchanged in the urine. An average dose of nitrofurantoin results in a urinary concentration of approximately 200 μg/mL. Excretion rate is linearly related to creatinine clearance. Clinical studies have shown that, under normal fasting conditions, the absorption of macrocrystalline nitrofurantoin is lower than that of microcrystalline form, and the absorption rate is slower. The presence of food in the intestine significantly delays the absorption of both formulations, increases the peak concentration of the macrocrystalline compound but not the peak concentration of the microcrystalline compound, improves the bioavailability of both formulations, and prolongs the duration of therapeutic urinary concentrations. The enhancing effect of food on absorption ranges from 20% to 400%, with the least soluble formulation showing the most significant effect. .../IT/ Low absorption efficiency from rectal suppositories...
Compared to physical mixtures, the absorption of nitrofurantoin from drug-deoxycholic acid coprecipitates is significantly increased, and faster absorption from coprecipitates is correlated with a faster in vitro dissolution rate. ...Excreted via canine bile, approximately one-third of the excrement is reabsorbed by the intestine within 3 hours. For more complete data on the absorption, distribution, and excretion of nitrofurantoin (13 types), please visit the HSDB record page. Metabolism/Metabolites: 0.8–1.8% of the dose is metabolized to aminofurantoin, and ≤0.9% is metabolized to other metabolites. Following a 0.200 mg/kg dose, 22% is excreted in the urine as N-(5-nitrofuranimino)-2-imidazolinone. /Excerpt from table/ Except in blood, it is rapidly degraded in all body tissues into inactive metabolites—hydroxylamine compounds and aminofuranaldehyde dihydronitrofuran acid. /Human, Oral/ Following intravenous infusion of nitrofurantoin (50 mg), 47% of the dose is excreted unchanged in the urine, and 1.2% is recovered as the reduced metabolite aminofurantoin. Nitrofurantoin is primarily metabolized in the liver. A small amount of the drug is reduced to aminofurantoin.

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Biological Half-Life
The half-life of nitrofurantoin is 0.72-0.78 hours.
The plasma half-life is 0.3 to 1 hour…
The half-life of nitrofurantoin in adults is 0.41 hours, and the half-life in 2-week-old rats is 0.95 hours.

Toxicity Summary
Identification: Nitrofurantoin is a urinary tract disinfectant and anti-infective agent. It is a lemon-yellow solid crystalline substance. Slightly soluble in water and ethanol, soluble in diethylformamide. It is used to treat primary or recurrent urinary tract infections caused by susceptible Gram-positive and Gram-negative bacteria, including most strains of Escherichia coli. Enterobacter and Klebsiella spp. are less susceptible, while Pseudomonas spp. and most Proteus strains are resistant to nitrofurantoin. Nitrofurantoin is ineffective against systemic bacterial infections in tissues other than the bloodstream or urinary tract. Human Exposure: Major Risks and Target Organs: The most common adverse reactions include anorexia, nausea, and vomiting. Nitrofurantoin has also been associated with neurological and central nervous system, hepatic, hematologic, pulmonary, and skin toxicities. Acute reactions due to nitrofurantoin overdose have not been reported, except for gastrointestinal symptoms. Toxic symptoms are usually due to hypersensitivity to the drug. Contraindications: Nitrofurantoin is contraindicated in patients with hypersensitivity to nitrofurantoin or nitrofuran derivatives. Nitrofurantoin is relatively contraindicated in patients with renal insufficiency, diabetes, electrolyte imbalance, and vitamin B deficiency, as the risk of peripheral neuropathy is increased in these conditions. If it must be used in these conditions, extreme caution should be exercised, and treatment should be discontinued immediately upon the onset of toxic symptoms. Hemolysis frequently occurs in patients with glucose-6-phosphate dehydrogenase deficiency taking nitrofurantoin. This effect is usually reversed upon discontinuation of the drug. Nitrofurantoin is contraindicated in women in full-term pregnancy (38-42 weeks of gestation) and should not be used during or before delivery to avoid hemolytic anemia in the newborn. Due to the immature enzyme system in newborns, the risk of hemolysis induced by nitrofurantoin is higher. Route of administration: Oral: This is the most common route of administration. Absorption route: Nitrofurantoin is readily absorbed from the gastrointestinal tract. Absorption mainly occurs in the small intestine. Microcrystalline drugs (suspensions, tablets, or capsules) are absorbed faster than macrocrystalline drugs (capsules). The presence of food in the gastrointestinal tract or delayed gastric emptying increases the degree of absorption (increases the rate of drug dissolution). Bioavailability is on average 87% when taken on an empty stomach and up to 94% when taken with food. Peak plasma concentration is usually reached 1 to 2 hours after a single oral dose. Distribution: Nitrofurantoin binds to plasma proteins at a rate of 25% to 90%. It crosses the placenta and is secreted into breast milk. Biological half-life: In adults with normal renal function, the plasma half-life after oral administration of a therapeutic dose is approximately 20 to 60 minutes. The half-life is prolonged in patients with impaired renal function. Metabolism: Approximately 2/3 of the dose is metabolized in the liver. A small amount is reduced to aminofurantoin. Elimination: 20% to 44% of the oral dose is excreted unchanged in the urine within 24 hours. 1% is excreted as aminofurantoin. Nitrofurantoin can be removed by dialysis. Mechanism of action: Toxicology: Nitrofurantoin causes liver injury (acute or chronic) through immune or metabolic mechanisms. Cholestatic jaundice and hepatocellular damage lead to elevated levels of alkaline phosphatase and aspartate aminotransferase. Nitrofurantoin has also been reported to induce the production of antinuclear antibodies and anti-smooth muscle antibodies. Pulmonary toxicity is attributed to the generation of superoxide anion radicals by nitrofurantoin, which triggers a chain reaction and uncontrolled destructive oxidation, suggesting that nitrofurantoin-mediated pulmonary oxidative damage may be due to direct cytotoxicity or indirectly through the recruitment of activated neutrophils. Nitrofurantoin can cause acute non-cardiogenic pulmonary edema or subacute interstitial pneumonia, the latter of which can progress to interstitial fibrosis. Acute reactions are generally considered to be hypersensitivity reactions. There is evidence that the damage may be related to immune mechanisms, and an increase in the number of T lymphocytes in bronchoalveolar lavage fluid is observed. Peripheral neuropathy is a complication of nitrofurantoin treatment, especially in patients with pre-existing renal impairment or diabetes. Nitrofurantoin induces degenerative changes in nerve cell axons, leading to sensory and motor dysfunction distal to the axon. Pharmacodynamics: The antibacterial or bactericidal effect of nitrofurantoin depends on its concentration and the sensitivity of the microorganism. Its antibacterial activity is enhanced under acidic pH conditions. It is believed that nitrofurantoin is reduced by bacterial flavin proteases to an active intermediate that inhibits the synthesis of proteins, DNA, RNA, and cell walls in microorganisms. Nitrofurantoin is effective against most Gram-positive and Gram-negative urinary tract pathogens, but its activity is generally lower against most Klebsiella spp., Enterobacter spp., Pseudomonas spp., and Proteus spp. strains. Toxicity: Human Data: Adults: There have been no reports of acute nitrofurantoin poisoning or deaths due to acute ingestion. The toxic or lethal dose of nitrofurantoin has not been determined. However, some adverse reactions and hypersensitivity reactions, including deaths, have been reported. The exposure time before the onset of acute pulmonary toxicity symptoms ranges from two to three days to several weeks. Teratogenicity: A case of a 14-month-old girl presenting with asymmetrical upper limb paralysis, with indications of early prenatal onset, has been reported. The suspected cause was the use of nitrofurantoin and bendazolam (Bendectin®) during early pregnancy. Mutagenicity: Data have shown that nitrofurantoin is mutagenic to human cells. Interactions: Food can significantly increase the bioavailability and duration of therapeutic concentration of nitrofurantoin. Uric acid excretion stimulants (such as probenecid or sulfinpyrazone) can inhibit renal excretion of nitrofurantoin, thereby increasing its plasma concentration, reducing its efficacy, and increasing its toxicity. Antacids: Magnesium trisilicate has been reported to reduce the rate and extent of nitrofurantoin absorption through an adsorption mechanism. In vitro studies have shown that nitrofurantoin can antagonize the antibacterial activity of quinolone drugs. This interaction may also occur in vivo. Drugs that acidify urine can reduce the excretion of nitrofurantoin. Major adverse reactions: The most common adverse reactions to nitrofurantoin are anorexia, nausea, and vomiting, which are dose-related. Peripheral neuropathy and optic neuritis are serious adverse reactions to nitrofurantoin and require immediate discontinuation. These adverse reactions are particularly likely to occur in patients with pre-existing renal impairment and vitamin B deficiency. Peripheral neuropathy has been reported in children aged 10 months to 18 years. Liver damage caused by nitrofurantoin is reversible upon discontinuation. Liver reactions are wide-ranging, from acute self-limiting hepatitis to chronic active hepatitis, and necrosis associated with long-term use. Pulmonary hypersensitivity reactions caused by nitrofurantoin can be life-threatening, and the drug should be discontinued immediately upon the onset of symptoms. Even after discontinuation, impaired lung function may persist. There have been reports of death due to cardiopulmonary failure and alveolar hemorrhage. Hematologic disorders—particularly noteworthy are reports of hemolytic anemia following nitrofurantoin use in patients with glucose-6-phosphate dehydrogenase (G-6-PD) deficiency. Other hematologic adverse reactions include leukopenia, granulocytopenia, agranulocytosis, thrombocytopenia, and aplastic anemia. Skin reactions include Stevens-Johnson syndrome and other rashes. Animal studies: Carcinogenicity: Nitrofurantoin does not appear to be carcinogenic. Long-term high-dose administration increases the incidence of ovarian cancer in mice. Carcinogenicity was found in female B6C3F mice and male F344/N rats. Teratogenicity: There is no evidence that nitrofurantoin is associated with birth defects in animals.

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Drug Interactions
Concomitant administration of probenecid, especially at high doses, reduces the renal clearance of nitrofurantoin and increases serum concentrations…This interaction may lead to nitrofurantoin-induced toxicity (e.g., polyneuropathy) or reduced efficacy of nitrofurantoin as an anti-infective for urinary tract infections.
Selenium supplementation has a protective effect against nitrofurantoin toxicity in vitamin E-deficient chicks.
Acetylsalicylic acid reduces the solubility of nitrofurantoin in artificial solvents. Intestinal fluid. Spectrophotometry showed that the two form a complex in solution. In in vitro absorption model studies, acetylsalicylic acid did not affect the diffusion rate constant of nitrofurantoin solution across artificial lipid membranes. Combined use studies in adults showed that acetylsalicylic acid reduced the total urinary excretion of nitrofurantoin.
Concomitant use of hemolytic agents and nitrofurantoin may increase the risk of toxic side effects.
For more complete data on interactions with nitrofurantoin (10 in total), please visit the HSDB record page.

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Non-human toxicity values
Oral LD50 in rats: 604 mg/kg
Oral LD50 in mice: 360 mg/kg

[1]. Nitrofurantoin revisited: a systematic review and meta-analysis of controlled trials. J Antimicrob Chemother. 2015 Sep;70(9):2456-64.

[2]. Garau J. Other antimicrobials of interest in the era of extended-spectrum beta-lactamases: fosfomycin, nitrofurantoin and tigecycline. Clin Microbiol Infect. 2008 Jan;14 Suppl 1:198-202.

[3]. Nitrofurantoin resistance mechanism and fitness cost in Escherichia coli. J Antimicrob Chemother. 2008 Sep;62(3):495-503.

[4]. Effects of the flavonoid chrysin on nitrofurantoin pharmacokinetics in rats: potential involvement of ABCG2. Drug Metab Dispos. 2007 Feb;35(2):268-74.

Therapeutic Uses
Anti-infective, Urinary System / SRP: Antibacterial Agent / Nitrofurantoin has bacteriostatic activity at concentrations of 5-10 μg/mL and bactericidal activity at 100 μg/mL, but its bactericidal activity in vivo is unknown. Its antibacterial activity is higher in acidic urine. Supersaturated nitrofurantoin solutions do not cause crystalluria. Nitrofurantoin is effective against a variety of common urinary tract pathogens, including Escherichia coli, Proteus spp., Pseudomonas spp., Enterobacter spp., and Staphylococcus, as well as Enterococcus, Streptococcus, Clostridium, and Bacillus subtilis. It is approved only for the treatment of urinary tract infections caused by microorganisms known to be susceptible to this drug. …It has been effectively used to prevent recurrent infections and to prevent bacteriuria after prostatectomy. For more complete data on the therapeutic uses of nitrofurantoin (8 types in total), please visit the HSDB record page.

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Drug Warnings
A single course of treatment should not exceed 14 days, and there should be a rest period between repeated courses. Nitrofurantoin is contraindicated in full-term pregnant women, patients with impaired renal function (creatinine clearance less than 40 mL/min), and infants under 1 month of age.
Maternal use generally compatible with breastfeeding: Nitrofurantoin: Can cause hemolysis in infants with glucose-6-phosphate dehydrogenase (G-6-PD) deficiency. (Excerpt from Table 6)
...Most Proteus and Pseudomonas species, as well as many Enterobacter and Klebsiella species, are resistant to nitrofurantoin. Due to rapid drug clearance, antibacterial concentrations may not be achieved in plasma after the recommended dose. In patients with impaired glomerular function, the efficacy of the drug may be reduced, and systemic toxicity may be increased.
Injectable nitrofurantoin sodium is only indicated for acutely ill patients who cannot tolerate oral nitrofurantoin. /Nitrofurantoin Sodium/
For more complete data on drug warnings for nitrofurantoin (31 in total), please visit the HSDB records page.

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Pharmacodynamics
Nitrofurantoin interferes with the life activities of bacteria, leading to bacterial death. Nitrofurantoin rapidly reaches therapeutic concentrations in urine and is rapidly eliminated.

C8H6N4O5

238.157

238.033

67-20-9

Nitrofurantoin-13C3;1217226-46-4;Nitrofurantoin sodium;54-87-5

6604200

Light yellow to yellow solid powder

1.8±0.1 g/cm3

268°C

1.745

-0.4

1

6

2

17

390

0

C1C(=O)NC(=O)N1/N=C/C2=CC=C(O2)[N+](=O)[O-]

NXFQHRVNIOXGAQ-YCRREMRBSA-N

InChI=1S/C8H6N4O5/c13-6-4-11(8(14)10-6)9-3-5-1-2-7(17-5)12(15)16/h1-3H,4H2,(H,10,13,14)/b9-3+

1-[(E)-(5-nitrofuran-2-yl)methylideneamino]imidazolidine-2,4-dione

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~100 mg/mL (~419.89 mM)

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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 (Please use freshly prepared in vivo formulations for optimal results.)