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Norfloxacin (AM-715; MK 0366; MK0366; AM715; MK-366; AM 715; MK366; MK 366; Noroxin; Chibroxin) is a broad-spectrum and synthetic chemotherapeuticantibiotic approved for the treatment of UTIs-urinary tract infections. It functions by blocking DNA gyrase and is effective against both Gram-positive and Gram-negative bacteria. Urinary tract infections, both simple and complex, are treated with norfloxacin. It is a first-generation synthetic fluoroquinolone that is authorized for the treatment of prostatitis, uTIs, and STDs, though the latter are no longer treated with it because of bacterial resistance.
Physicochemical Properties
| Molecular Formula | C16H18FN3O3 |
| Molecular Weight | 319.3308 |
| Exact Mass | 319.133 |
| Elemental Analysis | C, 60.18; H, 5.68; F, 5.95; N, 13.16; O, 15.03 |
| CAS # | 70458-96-7 |
| Related CAS # | 68077-27-0；118803-81-9 |
| PubChem CID | 4539 |
| Appearance | White to light yellow solid powder |
| Density | 1.3±0.1 g/cm3 |
| Boiling Point | 555.8±50.0 °C at 760 mmHg |
| Melting Point | 220°C |
| Flash Point | 289.9±30.1 °C |
| Vapour Pressure | 0.0±1.6 mmHg at 25°C |
| Index of Refraction | 1.595 |
| LogP | 0.82 |
| Hydrogen Bond Donor Count | 2 |
| Hydrogen Bond Acceptor Count | 7 |
| Rotatable Bond Count | 3 |
| Heavy Atom Count | 23 |
| Complexity | 519 |
| Defined Atom Stereocenter Count | 0 |
| SMILES | FC1C([H])=C2C(C(C(=O)O[H])=C([H])N(C([H])([H])C([H])([H])[H])C2=C([H])C=1N1C([H])([H])C([H])([H])N([H])C([H])([H])C1([H])[H])=O |
| InChi Key | OGJPXUAPXNRGGI-UHFFFAOYSA-N |
| InChi Code | InChI=1S/C16H18FN3O3/c1-2-19-9-11(16(22)23)15(21)10-7-12(17)14(8-13(10)19)20-5-3-18-4-6-20/h7-9,18H,2-6H2,1H3,(H,22,23) |
| Chemical Name | 1-ethyl-6-fluoro-4-oxo-7-piperazin-1-ylquinoline-3-carboxylic acid |
| Synonyms | MK-0366; Norfloxacin; AM-715; MK 0366; MK0366; AM715; MK-366; AM 715; MK366; MK 366; Noroxin; Chibroxin |
| HS Tariff Code | 2934.99.9001 |
| Storage |
Powder-20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition | Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs) |
Biological Activity
| Targets | Quinolone |
| ln Vitro | Norfloxacin (MK-0366) is a synthetic antibacterial chemotherapeutic agent that is occasionally used to treat both simple and complex urinary tract infections. Broad-spectrum antibiotic norfloxacin (MK-0366) is effective against both Gram-positive and Gram-negative bacteria. It stops cell division by blocking enzymes that are required to separate bacterial DNA, such as DNA gyrase, a type II topoisomerase, and topoisomerase IV. Currently, the adult population has three approved uses—one of which is restricted—and the other is ineffective because of bacterial resistance. |
| ADME/Pharmacokinetics |
Absorption, Distribution and Excretion Rapid Norfloxacin is eliminated through metabolism, biliary excretion, and renal excretion. It is expected to undergo both glomerular filtration and tubular secretion during renal excretion, as shown by its high renal clearance rate of approximately 275 mL/min. Norfloxacin crosses the placenta and is distributed into cord blood and amniotic fluid. It is not known whether the drug is distributed into milk. Norfloxacin was not detected in the milk of lactating women following a single 200-mg oral dose of the drug, but the possibility of distribution into milk following higher doses remains to be determined. Some other quinolones (e.g., ciprofloxacin, levofloxacin ofloxacin) are distributed into milk. In adults who received 400 mg of oral norfloxacin twice daily, prostatic tissue concentrations of the drug ranged from 0.24-4.65 ug/g in specimens obtained 1-4 hours after the second dose; concurrent serum concentrations ranged from 0.42-5.3 ug/mL. Norfloxacin is 10-15% bound to serum proteins. Biliary concentrations of norfloxacin may be up to 10 times higher than concurrent serum concentrations. In cholecystectomy patients who received a single 400-mg oral dose of norfloxacin prior to surgery, concentrations of the drug ranged from 0.6-15.6 ug/mL in gallbladder bile, from 0.4-7.5 mcg/g in gallbladder tissue, and from 0.4-1.8 ug/mL in serum in specimens obtained approximately 3.5-6 hours after the dose. There is limited information on the distribution of norfloxacin. Following oral administration in adults, norfloxacin is distributed into renal parenchyma, gallbladder, liver, prostatic tissue, testicles, seminal fluid, uterus, fallopian tubes, cervical and vaginal tissue, blister fluid, tonsils, maxillary sinus mucosa, sputum, and bile. For more Absorption, Distribution and Excretion (Complete) data for Norfloxacin (9 total), please visit the HSDB record page. Metabolism / Metabolites Via liver and kidney Norfloxacin is eliminated by renal and nonrenal mechanisms. The drug is partially metabolized by modification of the piperazinyl group to 6 metabolites, designated M-1, M-2, M-3, M-4(1), M-4(2), and M-5.2 Although some of the metabolites are microbiologically active, they are less active than the parent drug. It has been suggested that norfloxacin undergoes first-pass metabolism in the liver, but further study is needed to fully elucidate the metabolic fate of the drug. Pefloxacin, N-desmethyl is a known human metabolite of Pefloxacin. Biological Half-Life 3-4 hours In patients with impaired renal function, serum concentrations of norfloxacin are higher and its half-life is prolonged. In adults with renal impairment, the half-life of norfloxacin averaged 4.4, 6.6, or 7.6 hours in adults with creatinine clearances of 30-80, 10-29, or less than 10 mL/minute per 1.73 sq m, respectively. Limited data suggest that half-life of the drug is not substantially affected by hepatic impairment. The effective plasma or serum half-life of norfloxacin in adults with normal renal function is 2.3-4 hours. The effective half-life of the drug averages 4 hours in geriatric individuals 65-75 years of age with renal function normal for their age. |
| Toxicity/Toxicokinetics |
Hepatotoxicity Norfloxacin like other fluoroquinolones is associated with a low rate (1% to 3%) of serum enzyme elevations during therapy. These abnormalities are generally mild, asymptomatic and transient, resolving even with continuation of therapy. Norfloxacin has also been linked to rare but occasionally severe and even fatal cases of acute liver injury. While the numbers of cases have been few, the clinical pattern has been consistent with short latency period of 1 day to 3 weeks and abrupt onset of hepatocellular injury. The pattern of serum enzyme elevations can be either hepatocellular or cholestatic, cases with the shorter times to onset usually being more hepatocellular with markedly elevated ALT levels, and occasionally with rapid worsening of prothrombin time and signs of hepatic failure. The onset of illness may occur a few days after the medication is stopped. Many (but not all) cases have had allergic manifestations with fever, rash and eosinophilia. Autoantibodies are usually not present. Cholestatic and mixed patterns of injury have also been described particularly with delayed recognition of the liver injury. These features are typical of all fluoroquinolone associated hepatotoxicity and the injury is believed to be class specific. Likelihood score: C (probable rare cause of clinically apparent liver injury). Effects During Pregnancy and Lactation ◉ Summary of Use during Lactation No information is available on the clinical use of norfloxacin during breastfeeding; however, amounts in breastmilk appear to be low. Fluoroquinolones such as norfloxacin have traditionally not been used in infants because of concern about adverse effects on the infants' developing joints. However, more recent studies indicate little risk. In addition, the calcium in milk might prevent absorption of the small amounts of fluoroquinolones in milk, but insufficient data exist to prove or disprove this assertion. The serum and milk levels and oral bioavailability of norfloxacin are the lowest of any of the fluoroquinolones, so the risk to the infant should be minimal. Use of norfloxacin is acceptable in nursing mothers with monitoring of the infant for possible effects on the gastrointestinal flora, such as diarrhea or candidiasis (thrush, diaper rash). ◉ Effects in Breastfed Infants Relevant published information was not found as of the revision date. ◉ Effects on Lactation and Breastmilk Relevant published information was not found as of the revision date. Protein Binding 10 and 15% (Serum protein binding) Interactions Concomitant use of some quinolones (e.g., ciprofloxacin, norfloxacin) in patients receiving theophylline has resulted in increased plasma theophylline concentrations and decreased clearance of the drug and may increase the risk of theophylline-related adverse effects. There have been conflicting reports concerning the effect of norfloxacin on the pharmacokinetics of theophylline and additional study and experience are necessary to evaluate the interaction; however, the risk of norfloxacin inducing substantial alterations in theophylline pharmacokinetics appears to be less than with some other quinolones (e.g., ciprofloxacin). Concomitant administration of norfloxacin and an extended-release theophylline preparation to a limited number of individuals produced only slight increases in serum theophylline concentrations compared with that of some other quinolone derivatives. In other studies, concomitant administration of norfloxacin in patients stabilized on theophylline resulted in at most an 18% increase in plasma theophylline concentrations and a decrease in theophylline clearance of 5-28%. Some clinicians suggest that the interaction between norfloxacin and theophylline may not be clinically important in most patients. However, there have been reports of theophylline-related adverse effects in patients receiving norfloxacin concomitantly. Therefore, some clinicians suggest that norfloxacin be used with caution in patients receiving theophylline. The manufacturer of norfloxacin states that consideration should be given to monitoring plasma theophylline concentrations and theophylline dosage should be adjusted as required. Some quinolones (e.g., ciprofloxacin) also have been reported to alter the pharmacokinetics of caffeine, and the possibility of exaggerated or prolonged effects of caffeine during concomitant use with a quinolone should be considered. Concomitant administration of sucralfate may interfere with oral absorption of norfloxacin resulting in decreased serum and urine concentrations of the quinolone, and some clinicians state that concomitant use of ofloxacin with sucralfate is not recommended. If concomitant use of ofloxacin and sucralfate is necessary, the manufacturer and some clinicians recommend that norfloxacin doses should be taken at least 2 hours before or after sucralfate doses. Concomitant administration of probenecid substantially decreases urinary excretion of norfloxacin, possibly by blocking renal tubular secretion of the anti-infective, but serum concentrations and half-life of norfloxacin generally are not affected. In vitro, chloramphenicol, rifampin, or tetracycline can inhibit the bactericidal activity of norfloxacin. In an in vitro study, the combination of norfloxacin and chloramphenicol or tetracycline was antagonistic against all Salmonella isolates tested. In an in vitro study using strains of Ps. aeruginosa resistant to aminoglycosides and carbenicillin, the antibacterial activities of imipenem and norfloxacin were synergistic or partially synergistic against about one-third and indifferent against about two-thirds of strains tested; antagonism did not occur. In vitro studies using both gram-positive and gram-negative bacteria indicate that neither synergism nor antagonism occurs when norfloxacin is used in conjunction with a beta-lactam antibiotic (e.g., ampicillin, cefotaxime, cefoxitin). For more Interactions (Complete) data for Norfloxacin (16 total), please visit the HSDB record page. Non-Human Toxicity Values LD50 Mouse im 470 mg/kg LD50 Mouse iv 222 mg/kg LD50 Mouse oral 4 g/kg LD50 Rat iv 245 mg/kg |
| References |
[1]. Fluoroquinolone-resistant Campylobacter species and the withdrawal of fluoroquinolones from use in poultry: a public health success story. Clin Infect Dis. 2007 Apr 1;44(7):977-80. Epub 2007 Feb 14. [2]. Norfloxacin: more than 20 years of clinical use, the results and place among fluoroquinolones in modern chemotherapy for infections. Antibiot Khimioter. 2003;48(9):28-36. [3]. Quinolones for uncomplicated acute cystitis in women. Cochrane Database Syst Rev. 2006 Jul 19;(3):CD003597. |
| Additional Infomation |
Norfloxacin is a quinolinemonocarboxylic acid with broad-spectrum antibacterial activity against most gram-negative and gram-positive bacteria. Norfloxacin is bactericidal and its mode of action depends on blocking of bacterial DNA replication by binding itself to an enzyme called DNA gyrase. It has a role as an antibacterial drug, a DNA synthesis inhibitor, a xenobiotic and an environmental contaminant. It is a quinolinemonocarboxylic acid, a N-arylpiperazine, a quinolone, a quinolone antibiotic and a fluoroquinolone antibiotic. A synthetic fluoroquinolone (fluoroquinolones) with broad-spectrum antibacterial activity against most gram-negative and gram-positive bacteria. Norfloxacin inhibits bacterial DNA gyrase. Norfloxacin is a Quinolone Antimicrobial. Norfloxacin is a first generation fluoroquinolone that is typically used to treated urinary tract infections and prostatitis. Norfloxacin has been linked to rare instances of acute hepatocellular injury. Norfloxacin has been reported in Bacillus subtilis and Caloboletus radicans with data available. Norfloxacin is a synthetic, broad-spectrum fluoroquinolone with antibacterial activity. Norfloxacin inhibits activity of DNA gyrase, thereby blocking bacterial DNA replication. Norfloxacin concentrates in the renal tubules and bladder and is bactericidal against a wide range of aerobic gram-positive and gram-negative organisms. A synthetic fluoroquinolone (FLUOROQUINOLONES) with broad-spectrum antibacterial activity against most gram-negative and gram-positive bacteria. Norfloxacin inhibits bacterial DNA GYRASE. See also: Norfloxacin hydrochloride (is active moiety of). Drug Indication For the treatment of urinary tract infection FDA Label Mechanism of Action The bactericidal action of Norfloxacin results from inhibition of the enzymes topoisomerase II (DNA gyrase) and topoisomerase IV, which are required for bacterial DNA replication, transcription, repair, and recombination. Norfloxacin is a broad-spectrum antibiotic agent that is shown to be effective against various Gram-positive and Gram-negative bacterial species. The fluorine atom at the 6 position increases potency against gram-negative organisms, and the piperazine moiety at the 7 position is responsible for anti-pseudomonal activity Norfloxacin usually is bactericidal in action. Like other fluoroquinolone anti-infectives, norfloxacin inhibits DNA synthesis in susceptible organisms via inhibition of type II DNA topoisomerases (DNA gyrase, topoisomerase IV). Fluoroquinolones prolong the QT interval by blocking voltage-gated potassium channels, especially the rapid component of the delayed rectifier potassium current I(Kr), expressed by HERG (the human ether-a-go-go-related gene). According to the available case reports and clinical studies, moxifloxacin carries the greatest risk of QT prolongation from all available quinolones in clinical practice and it should be used with caution in patients with predisposing factors for Torsades de pointes (TdP). Therapeutic Uses Anti-Bacterial Agents; Enzyme Inhibitors; Nucleic Acid Synthesis Inhibitors Oral norfloxacin is used for the treatment of prostatitis caused by E. coli. /Included in US product label/ Oral norfloxacin is used in adults for the treatment of complicated UTIs caused by susceptible E. coli, K. pneumoniae, P. mirabilis, Ps. aeruginosa, S. marcescens, or E. faecalis. /Included in US product label/ Oral norfloxacin is used in adults for the treatment of uncomplicated urinary tract infections (UTIs) (including cystitis) caused by susceptible Citrobacter freundii, Enterobacter aerogenes, E. cloacae, Escherichia coli, Klebsiella pneumoniae, ... Proteus mirabilis, P. vulgaris, ... Pseudomonas aeruginosa, ... . The drug also is used orally in adults for the treatment of uncomplicated UTIs caused by susceptible Staphylococcus aureus, S. epidermidis, S. saprophyticus, Streptococcus agalactiae (group B streptococci), or Enterococcus faecalis. /Included in US product label/ For more Therapeutic Uses (Complete) data for Norfloxacin (10 total), please visit the HSDB record page. Drug Warnings WARNING: Fluoroquinolones, including Noroxin, are associated with an increased risk of tendinitis and tendon rupture in all ages. This risk is further increased in older patients usually over 60 years of age, in patients taking corticosteroid drugs, and in patients with kidney, heart or lung transplants. WARNING: Fluoroquinolones, including Noroxin, may exacerbate muscle weakness in persons with myasthenia gravis. Avoid Noroxin in patients with known history of myasthenia gravis Serious and occasionally fatal hypersensitivity (anaphylactic) reactions, some following the first dose, have been reported in patients receiving quinolone therapy, including Noroxin. Some reactions were accompanied by cardiovascular collapse, loss of consciousness, tingling, pharyngeal or facial edema, dyspnea, urticaria and itching. Only a few patients had a history of hypersensitivity reactions. If an allergic reaction to norfloxacin occurs, discontinue the drug. Serious acute hypersensitivity reactions require immediate emergency treatment with epinephrine. Oxygen, intravenous fluids, antihistamines, corticosteroids, pressor amines, and airway management, including intubation, should be administered as indicated. Other serious and sometimes fatal events, some due to hypersensitivity, and some due to uncertain etiology, have been reported rarely in patients receiving therapy with quinolones, including Noroxin. These events may be severe and generally occur following the administration of multiple doses. Clinical manifestations may include one or more of the following: fever, rash or severe dermatologic reactions (e.g., toxic epidermal necrolysis, Stevens-Johnson syndrome); vasculitis; arthralgia; myalgia; serum sickness; allergic pneumonitis; interstitial nephritis; acute renal insufficiency or failure; hepatitis; jaundice; acute hepatic necrosis or failure; anemia, including hemolytic and aplastic; thrombocytopenia, including thrombotic thrombocytopenic purpura; leukopenia; agranulocytosis; pancytopenia; and/or other hematologic abnormalities. For more Drug Warnings (Complete) data for Norfloxacin (24 total), please visit the HSDB record page. Pharmacodynamics Norfloxacin is a quinolone/fluoroquinolone antibiotic. Norfloxacin is bactericidal and its mode of action depends on blocking of bacterial DNA replication by binding itself to an enzyme called DNA gyrase, which allows the untwisting required to replicate one DNA double helix into two. Notably the drug has 100 times higher affinity for bacterial DNA gyrase than for mammalian. |
Solubility Data
| Solubility (In Vitro) |
DMSO : 3~5 mg/mL (9.4~15.7 mM) Water : <1 mg/mL Ethanol : <1 mg/mL |
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 0.5 mg/mL (1.57 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 5.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 0.5 mg/mL (1.57 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 5.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 3.1316 mL | 15.6578 mL | 31.3156 mL | |
| 5 mM | 0.6263 mL | 3.1316 mL | 6.2631 mL | |
| 10 mM | 0.3132 mL | 1.5658 mL | 3.1316 mL |