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
Nitrofurantoin reaches a Cmax of 0.875-0.963mg/L with an AUC of 2.21-2.42mg\*h/L. It is 38.8-44.3% bioavailable. Taking nitrofurantoin with food increases the absorption and duration of therapeutic concentrations in the urine.
27-50% of an oral dose is excreted in the urine as unchanged nitrofurantoin. 90% of the total dose is eliminated in the urine.
Data regarding the volume of distribution in humans is scarce but it has been reported as 0.46L/kg in dogs.
The clearance of nitrofurantoin is 16.7-19.4L/h.
.../IT/ IS RAPIDLY & COMPLETELY ABSORBED FROM GI TRACT. ... PLASMA HALF-LIFE IS 0.3 TO 1 HR; ABOUT 40% IS EXCRETED UNCHANGED INTO URINE. AVG DOSE OF NITROFURANTOIN YIELDS URINE CONCN OF APPROX 200 UG/ML. ... RATE OF EXCRETION IS LINEARLY RELATED TO CREATININE CLEARANCE...
CLINICAL STUDIES...INDICATE THAT IN NORMAL FASTING INDIVIDUALS, LESS NITROFURANTOIN IS ABSORBED & AT SLOWER RATE FROM MACROCRYSTALLINE THAN MICROCRYSTALLINE FORM. PRESENCE OF FOOD IN INTESTINE DELAYS ABSORPTION OF BOTH FORMS APPRECIABLY, INCR PEAK LEVELS OF MACROCRYSTALLINE COMPD, BUT NOT MICROCRYSTALLINE COMPD, ENHANCES BIOAVAILABILITY OF BOTH FORMS, & PROLONGS DURATION OF THERAPEUTIC URINARY CONCN.
ENHANCEMENT OF...ABSORPTION BY FOOD RANGED FROM 20 TO 400%, WITH GREATEST EFFECT OCCURRING WITH LEAST SOLUBLE DOSAGE FORMS. .../IT/ IS INEFFICIENTLY ABSORBED FROM RECTAL SUPPOSITORIES...
NITROFURANTOIN ABSORPTION IS SIGNIFICANTLY INCR IN MAN FROM A DRUG-DEOXYCHOLIC ACID CO-PRECIPITATE COMPARED WITH PHYS MIXT, & FASTER ABSORPTION...FROM CO-PRECIPITATE WAS ASSOCIATED WITH FASTER IN VITRO DISSOLUTION RATE. ... EXCRETED IN BILE OF DOGS & ABOUT 1/3 OF THAT EXCRETED IS REABSORBED FROM INTESTINE WITHIN 3 HR.
For more Absorption, Distribution and Excretion (Complete) data for NITROFURANTOIN (13 total), please visit the HSDB record page.

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Metabolism / Metabolites
0.8-1.8% of a dose is metabolized to aminofurantoin, and ≤0.9% of a dose is metabolized to other metabolites.
AFTER DOSE OF 0.200 MG/KG, 22% IS EXCRETED IN URINE AS N-(5-NITROFURFURYLIDENEAMINO)-2-IMIDAZOLINE-ONE. /FROM TABLE/
READILY DEGRADED BY ALL /BODY/ TISSUES (EXCEPT BLOOD) INTO INACTIVE METABOLITES-HYDROXYLAMINO COMPD & AMINOFURALDEHYDENITROFURIC ACID. /HUMAN, ORAL/
AFTER NITROFURANTOIN (50 MG) IV INFUSION, 47% OF THE DOSE WAS EXCRETED UNCHANGED IN THE URINE AND 1.2% WAS RECOVERED AS THE REDUCED METABOLITE AMINOFURANTOIN.
Nitrofurantoin is partially metabolized, mainly in the liver. A small fraction of the drug is reduced to form aminofurantoin.

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Biological Half-Life
The half life of nitrofurantoin is 0.72-0.78h.
PLASMA HALF-LIFE IS 0.3 TO 1 HR...
NITROFURANTOIN HALF-LIFE WAS 0.41 HOURS IN ADULTS AND 0.95 HOURS IN 2-WEEK-OLD RATS.

Toxicity Summary
IDENTIFICATION: Nitrofurantoin is an urninary antiseptic and antiinfective drug. It is a lemon yellow solid crystalline material. It is very sightly soluble in water and alcohol. It is soluble in diethylformamide. In the treatment of initial or recurrent urinary tract infections caused by susceptible gram positive and gram negative bacteria including most strains of Escherischia coli. Enterobacter and Klebsiella species are less susceptible and Pseudomonas and most strains of Proteus are resistant to nitrofurantoin. Nitrofurantoin is ineffective in systemic bacterial infections in blood or tissues outside the urinary tract. HUMAN EXPOSURE: Main risks and target organs: The most frequent adverse effects include anorexia, nausea and vomiting. Nitrofurantoin has also been associated with neurological and central nervous system, hepatic, hematological, pulmonary and dermatological toxicity. Apart from gastrointestinal tract symptoms, acute reactions as a result of overdosage of nitrofurantoin have not been reported. Symptoms of toxicity are generally due to hypersensitivity to the drug. Contraindications: Nitrofurantoin is contraindicated in patients who are hypersensitive to the drug or to furan derivatives. It is also relatively contraindicated in renal impairment, diabetes mellitus, electrolyte imbalance, vit.B deficiency as there is an increased risk of developing peripheral neuropathy in these situations. If it has to be used in these cases, extreme care should be taken and treatment stopped at the first sign of toxicity. Hemolysis frequently occurs in Glucose-6-phosphate dehydrogenase deficient patients who take nitrofurantoin. Discontinuation of the drug will often reverse this effect. Nitrofurantoin is contraindicated in pregnant women at term (38-42 weeks gestation) and it should not be administered during labor or just prior to labor to avoid precipitation of hemolytic anemia in the neonate. Neonates are at high risk of hemolysis induced by nitrofurantoin due to their immature enzyme systems. Routes of exposure: Oral: This is the most common route of entry. Absorption by route of exposure: Nitrofurantoin is readily absorbed from the gastrointestinal tract. Absorption occurs mainly in the small intestine. The microcrystalline form of the drug (in suspension, tablets or capsules) is absorbed faster than the macrocrystalline form (in capsules). Presence of food in the gastrointestinal tract or delayed gastric emptying increases the extent of absorption (enhancing the dissolution rate of the drug). Bioavailability is a mean of 87% when taken on an empty stomach, and increases to a mean of 94% when ingested with food. Peak plasma concentrations following a single oral dose are usually attained at 1 to 2 hours after ingestion. Distribution by route of exposure: Nitrofurantoin is 25 to 90% bound to plasma protein. It crosses the placenta and is excreted in the milk. Biological half-life by route of exposure: The plasma half life is approximately 20 to 60 minutes in adults with normal renal function after a therapeutic oral dose. The half-life is prolonged in patients with impaired renal function. Metabolism: Approximately 2/3 of a dose is metabolized in the liver. A small fraction is reduced to aminofurantoin. Elimination by route of exposure: 20 to 44% of an oral dose is excreted unchanged in the urine within 24 hours. 1% is excreted as aminofurantoin. Nitrofurantoin is dialyzable. Mode of action: Toxicodynamics: Nitrofurantoin causes hepatic injury (acute and chronic) through an immunological or metabolic mechanism. Cholestatic jaundice and hepatocellular damage result in elevation of alkaline phosphatase and aspartate transaminase levels. Development of antinuclear antibodies and antismooth muscle antibodies has also been reported. Pulmonary toxicity is attributed to nitrofurantoin production of superoxide anion free radicals with subsequent chain reactions and uncontrolled destructive oxidation, suggested that nitrofurantoin mediated oxidant injury to the lung may be due to direct cytotoxicity or indirectly through recruitment of activated neutrophils. Nitrofurantoin can cause an acute non-cardiogenic pulmonary edema, or subacute interstitial pneumonitis which may progress to interstitial fibrosis. The acute reaction is generally considered to be a hypersensitivity reaction. There is evidence pointing to an immunological mechanism for injury and an increase in T-Lymphocytes in broncheo-alveolar lavage. Peripheral neuropathy is a complication of nitrofurantoin therapy especially in patients with pre-existing renal impairment or diabetes mellitus. Nitrofurantoin triggers a degenerative process in the nerve cell axon with subsequent impairment of sensation and motor strength in the distal extent of the axonal process. Pharmacodynamics: Nitrofurantoin is bacteriostatic or bacteriocidal depending on the concentration and the susceptibility of the microorganism. Its antibacterial activity is enhanced in an acidic pH. It is thought that nitrofurantoin is reduced by bacterial flavoprotein enzymes to an active intermediate which inhibits the microorganism's proteins, DNA, RNA and cell wall synthesis. Nitrofurantoin is active against most strains of Gram positive and Gram negative urinary tract pathogens but generally less active against most strains of Klebsiella, Enterobacter, Pseudomonas and Proteus. Toxicity: Human data: Adults: Acute toxic exposures to nitrofurantoin have not been reported and there have been no acute ingestions causing fatalities. No toxic or lethal levels have been determined for nitrofurantoin. However there are a number of adverse effects and hypersensitivity reactions reported which have included fatalities. The duration of exposure before the onset of symptoms of acute pulmonary toxicity varies from two or three days to several weeks. Teratogenicity: case of a 14 month old girl with asymmetrical paralysis limited to the upper limbs with signs suggesting an early prenatal onset was reported. Nitrofurantoin and Bendectin (R) taken during early pregnancy were suspected to be the cause. Mutagenicity: There are data demonstrating mutagenicity in human cells Interactions: Food significantly enhances the bioavailability and duration of the therapeutic concentration of nitrofurantoin. Uricosuric agents (probenecid or sulfinpyrazone) may inhibit renal excretion of nitrofurantoin and hence increase its plasma level, reduce its effectiveness, and increase its toxicity. Antacids: specifically magnesium trisilicate were reported to decrease the rate and extent of nitrofurantoin absorption through an adsorption mechanism. Quinolones antibacterial activity in vitro is antagonized by nitrofurantoin. It is possible that this interaction could occur in vivo as well. Drugs which acidify the urine decrease the excretion of nitrofurantoin. Main adverse effects: The most frequent adverse effects of nitrofurantoin are anorexia, nausea, and vomiting, which are dose related. Peripheral polyneuropathy and optic neuritis are serious adverse effects of nitrofurantoin and call for immediate withdrawal of the drug. They occur especially in pre-existing renal impairment and the presence of vitamin B deficiency. Peripheral neuropathy was reported in 10 month to 18 year old children. Hepatic damage with nitrofurantoin is reversible on discontinuation of the drug. Hepatic reactions range from acute self-limiting hepatitis to chronic active hepatitis and necrosis associated with long term use. Pulmonary hypersensitivity reactions to nitrofurantoin can be life threatening and nitrofurantoin should be stopped immediately on occurance of symptoms. Impaired pulmonary function may remain even after cessation of therapy. Deaths as a result of cardiopulmonary collapse and of alveolar hemorrhage have been reported. Hematological disorders - and of special significance, hemolytic anaemia associated with use in patients with G-6-PD deficiency have been reported in association with nitrofurantoin use. Additional hematologic effects include leukopenia, granulocytopenia, agranulocytosis, thrombocytopenia, and aplastic anemia. Dermatologic reactions include Stevens Johnson syndrome and other rashes. ANIMAL STUDIES: Carcinogenicity: Nitrofurantoin does not appear to be carcinogenic. There is increased ovarian cancer in mice with chronic, high dose administration. It was found to be carcinogenic in B6C3F female mice and in F344/N male rats. Teratogenicity: There is no evidence to link nitrofurantoin to birth defects in animals.

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Interactions
CONCURRENT ADMIN OF PROBENECID, PARTICULARLY IN HIGH DOSES, DECR RENAL CLEARANCE OF NITROFURANTOIN & INCR SERUM LEVEL... INTERACTION MAY LEAD TO NITROFURANTOIN-INDUCED TOXICITY (EG, POLYNEUROPATHIES) OR DECR NITROFURANTOIN EFFICACY AS URINARY TRACT ANTI-INFECTIVE AGENT.
IN VITAMIN E-DEFICIENT CHICKS, ADMINISTRATION OF SELENIUM HAD A PROTECTIVE EFFECT AGAINST NITROFURANTOIN TOXICITY.
ACETYLSALICYLIC ACID REDUCED THE SOLUBILITY OF NITROFURANTOIN IN ARTIFICIAL INTESTINAL JUICE. SPECTROPHOTOMETRY INDICATED FORMATION OF A COMPLEX BETWEEN THE TWO IN SOLUTION. IN MODEL ABSORPTION STUDIES IN VITRO, ACETYLSALICYLIC ACID DID NOT AFFECT THE DIFFUSION RATE CONSTANT OF NITROFURANTOIN IN SOLUTION ACROSS AN ARTIFICIAL LIPID MEMBRANE. COADMINISTRATION STUDIES IN ADULT HUMANS SHOWED THAT ACETYLSALICYLIC ACID REDUCED THE TOTAL URINARY EXCRETION OF NITROFURANTOIN.
Concurrent use of /hemolytics/ with nitrofurantoin may increase the potential for toxic side effects.
For more Interactions (Complete) data for NITROFURANTOIN (10 total), please visit the HSDB record page.

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Non-Human Toxicity Values
LD50 Rat oral 604 mg/kg
LD50 Mouse oral 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 Agents, Urinary /SRP: Antibacterial/
NITROFURANTOIN IS BACTERIOSTATIC AT CONCN OF 5-10 UG/ML & BACTERICIDAL AT 100 UG/ML, BUT IT IS NOT KNOWN WHETHER BACTERICIDAL ACTION OCCURS IN VIVO. ANTIBACTERIAL ACTIVITY IS HIGHER IN ACIDIC URINE. ...SUPERSATURATED SOLN OF NITROFURANTOIN DO NOT CAUSE CRYSTALLURIA.
NITROFURANTOIN IS ACTIVE AGAINST MANY STRAINS OF COMMON URINARY TRACT PATHOGENS E COLI, PROTEUS SPECIES, PSEUDOMONAS...ENTEROBACTER, AND STAPHYLOCOCCI, AS WELL AS ENTEROCOCCI, STREPTOCOCCI, CLOSTRIDIA, & BACILLUS SUBTILIS.
...APPROVED ONLY FOR TREATMENT OF URINARY TRACT INFECTIONS CAUSED BY MICROORGANISMS THAT ARE KNOWN TO BE SENSITIVE TO DRUG. ... IT HAS BEEN USED EFFECTIVELY TO PREVENT RECURRENT INFECTIONS & FOR PREVENTION OF BACTERIURIA AFTER PROSTATECTOMY.
For more Therapeutic Uses (Complete) data for NITROFURANTOIN (8 total), please visit the HSDB record page.

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Drug Warnings
A COURSE OF THERAPY SHOULD NOT EXCEED 14 DAYS, & REPEATED COURSES SHOULD BE SEPARATED BY REST PERIODS. ... PREGNANT WOMEN AT TERM, INDIVIDUALS WITH IMPAIRED RENAL FUNCTION (CREATININE CLEARANCE LESS THAN 40 ML/MIN), & CHILDREN BELOW 1 MONTH OF AGE SHOULD NOT RECEIVE NITROFURANTOIN.
Maternal Medication Usually Compatible with Breast-Feeding: Nitrofurantoin: Hemolysis in infant with glucose-6-phosphate dehydrogenase (G-6-PD) deficiency. /from Table 6/
...MOST SPECIES OF PROTEUS & PSEUDOMONAS & MANY OF ENTEROBACTER & KLEBSIELLA ARE RESISTANT. ANTIBACTERIAL CONCN ARE NOT ACHIEVED IN PLASMA FOLLOWING INGESTION OF RECOMMENDED DOSES, BECAUSE DRUG IS RAPIDLY ELIMINATED. ...IN PT WITH IMPAIRED GLOMERULAR FUNCTION EFFICACY OF DRUG MAY BE DECR & SYSTEMIC TOXICITY INCR.
INJECTION OF NITROFURANTOIN SODIUM IS INDICATED ONLY FOR USE IN ACUTELY ILL PT WHO CANNOT TOLERATE ORAL NITROFURANTOIN. /SODIUM NITROFURANTOIN/
For more Drug Warnings (Complete) data for NITROFURANTOIN (31 total), please visit the HSDB record page.

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Pharmacodynamics
Nitrofurantoin interferes with vital processes in bacteria, which leads to their death. Nitrofurantoin rapidly reaches therapeutic concentrations in the urine and is also cleared rapidly.

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.)