Topoisomerase IV

Ciprofloxacin (Bay-09867) (30 mg/kg; i.p.; for 24 hours; BALB/c mice) provides protection against Y. pestis in murine model of pneumonic plague[3]. Ciprofloxacin (Bay-09867) (100 mg/kg; i.e., daily, for 4 weeks; C57BL/6J mice) increases the incidence of aortic dissection and rupture and accelerates the enlargement of the aortic root by decreasing the level of LOX and increasing the activity and levels of MMP in the aortic wall[4]. Ciprofloxacin (Bay-09867) (100 mg/kg; i.e., daily, for 4 weeks; C57BL/6J mice) causes mitochondrial dysfunction, cytosolic DNA sensor signaling activation, and DNA damage and release into the cytosol. Apoptosis and necroptosis in the aortic wall are increased by ciprofloxacin lactate[4].

Cell Line: Tendon cells
Concentration: 5, 10, 20 and 50 μg/mL
Incubation Time: 24 hours
Result: Decreased the cellularity of tendon cells.

Absorption, Distribution and Excretion
A 250mg oral dose of ciprofloxacin reaches an average maximum concentration of 0.94mg/L in 0.81 hours with an average area under the curve of 1.013L/h\*kg. The FDA reports an oral bioavailability of 70-80% while other studies report it to be approximately 60%. An early review of ciprofloxacin reported an oral bioavailability of 64-85% but recommends 70% for all practical uses.
27% of an oral dose was recovered unmetabolized in urine compared to 46% of an intravenous dose. Collection of radiolabelled ciprofloxacin resulted in 45% recovery in urine and 62% recovery in feces.
Cirpofloxacin follws a 3 compartment distribution model with a central compartment volume of 0.161L/kg and a total volume of distribution of 2.00-3.04L/kg.
The average renal clearance after a 250mg oral dose is 5.08mL/min\*kg. Following a 100mg intravenous dose, the average total clearance is 9.62mL/min\*kg, average renal clearance is 4.42mL/min\*kg, and average non renal clearance is 5.21mL/min\*kg.
Based on population pharmacokinetics, bioavailability of ciprofloxacin oral suspension in children is approximately 60%. Following a single oral dose of 10 mg/kg of ciprofloxacin given as the oral suspension to children 4 months to 7 years of age, the mean peak plasma concentration was 2.4 ug/mL. There was no apparent age dependence and no increase in peak plasma concentrations following multiple doses.
When extended-release tablets containing ciprofloxacin hydrochloride (ProQuin XR) are administered with food, approximately 87% of the drug is gradually released from the tablet over a 6- hour period. When administered following a meal, peak plasma concentrations are attained approximately 4.5-7 hours after the dose. Bioavailability is substantially lower if ProQuin XR tablets are given while fasting. In healthy adults receiving ProQuin XR extended-release tablets in a dosage of 500 mg once daily given following a standardized meal, peak plasma concentrations at steady state (day 3) average 0.82 mcg/mL and are attained 6.1 hours after the dose. /Ciprofloxacin hydrochloride/
Following oral administration of extended-release tablets containing ciprofloxacin hydrochloride and base (Cipro XR), peak plasma concentrations of ciprofloxacin are attained within 1-4 hours. Cipro XR tablets contain approximately 35% of the dose within an immediate-release component; the remaining 65% of the dose is contained in a slow-release matrix. Oral administration of ciprofloxacin 500 mg daily as Cipro XR extended-release tablets or 250 mg twice daily as conventional tablets results in steady-state mean peak plasma concentrations of 1.59 or 1.14 ug/mL, respectively; however, the area under the concentration-time curve (AUC) is similar with both regimens. /Ciprofloxacin hydrochloride/
Peak serum concentrations of ciprofloxacin and AUCs of the drug are slightly higher in geriatric patients than in younger adults; this may occur because of increased bioavailability, reduced volume of distribution, and/or reduced renal clearance in these patients. Single-dose oral studies using ciprofloxacin conventional tablets and single- and multiple-dose IV studies indicate that, compared with younger adults, peak plasma concentrations are 16-40% higher, mean AUC is approximately 30% higher, and elimination half-life is prolonged approximately 20% in individuals older than 65 years of age. These differences can be at least partially attributed to decreased renal clearance in this age group and are not clinically important.
For more Absorption, Distribution and Excretion (Complete) data for CIPROFLOXACIN (18 total), please visit the HSDB record page.

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Metabolism / Metabolites
Ciprofloxacin is primarily metabolized by CYP1A2. The primary metabolites oxociprofloxacin and sulociprofloxacin make up 3-8% of the total dose each. Ciprofloxacin is also converted to the minor metabolites desethylene ciprofloxacin and formylciprofloxacin. These 4 metabolites account for 15% of a total oral dose. There is a lack of available data on the enzymes and types of reactions involved in forming these metabolites.
The drug is partially metabolized in the liver by modification of the piperazinyl group to at least 4 metabolites. These metabolites, which have been identified as desethyleneciprofloxacin (M1), sulfociprofloxacin (M2), oxociprofloxacin (M3), and N-formylciprofloxacin (M4), have microbiologic activity that is less than that of the parent drug but may be similar to or greater than that of some other quinolones (e.g., M3 and M4 are comparable to norfloxacin for certain organisms).
Hepatic. Four metabolites have been identified in human urine which together account for approximately 15% of an oral dose. The metabolites have antimicrobial activity, but are less active than unchanged ciprofloxacin.
Route of Elimination: Approximately 40 to 50% of an orally administered dose is excreted in the urine as unchanged drug.
Half Life: 4 hours

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Biological Half-Life
The average half life following a 250mg oral dose was 4.71 hours and 3.65 hours following a 100mg intravenous dose. Generally the half life is reported as 4 hours.
The serum elimination half-life of ciprofloxacin in adults with normal renal function is 3-7 hours. Following IV administration in healthy adults, the distribution half-life of ciprofloxacin averages 0.18-0.37 hours and the elimination half-life averages 3-4.8 hours. The elimination half-life of the drug is slightly longer in geriatric adults than in younger adults, and ranges from 3.3-6.8 hours in adults 60-91 years of age with renal function normal for their age. Based on population pharmacokinetic analysis of pediatric patients with various infections, the predicted mean half-life of ciprofloxacin in children is approximately 4-5 hours. In patients with impaired renal function, serum concentrations of ciprofloxacin are higher and the half-life prolonged. In adults with creatinine clearances of 30 mL/minute or less, half-life of the drug ranges from 4.4-12.6 hours.
t1/2 for ciprofloxacin- normal: 4 (hr), anephric: 8.5 (hr) /from table/

Toxicity Summary
The bactericidal action of ciprofloxacin results from inhibition of the enzymes topoisomerase II (DNA gyrase) and topoisomerase IV, which are required for bacterial DNA replication, transcription, repair, strand supercoiling repair, and recombination.

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Interactions
Serious and fatal reactions have been reported in patients receiving concurrent administration of ciprofloxacin and theophylline. These reactions have included cardiac arrest, seizure, status epilepticus, and respiratory failure. Although similar serious adverse effects have been reported in patients receiving theophylline alone, the possibility that these reactions may be potentiated by ciprofloxacin cannot be eliminated. If concomitant use cannot be avoided, serum levels of theophylline should be monitored and dosage adjustments made as appropriate.
... The effects of aluminum hydroxide ... and calcium carbonate ... on the bioavailability of ciprofloxacin /was determined in/ ... a 3 way randomized, crossover study was concluded in 12 healthy male volunteers (ages 21-45 yr) that consisted of 3 treatments: 750 mg ciprofloxacin alone, 750 mg ciprofloxacin with 3.4 g calcium carbonate or 1.8 g aluminum hydroxide admin 5 min before ciprofloxacin. The relative bioavailability of ciprofloxacin was reduced to 60% and 15% of control values when given with calcium carbonate and aluminum hydroxide, respectively. ... It was concluded that antacids containing either aluminum or calcium should not be given concurrently with ciprofloxacin.
Ciprofloxacin, given to a patient successfully treated with methadone for more than 6 yrs, caused profound sedation, confusion, & respiratory depression. We suggest that this was caused by ciprofloxacin inhibition of CYP1A2 & CYP3A4 activity, 2 of the cytochrome p450 isozymes involved in the metab of methadone.
Synergism does not occur in vitro when ciprofloxacin is used in conjunction with vancomycin against Staphylococcus epidermidis, S. aureus (including oxacillin-resistant S. aureus), Corynebacterium, or Listeria monocytogenes.
For more Interactions (Complete) data for CIPROFLOXACIN (35 total), please visit the HSDB record page.

[1]. Ciprofloxacin-mediated cell proliferation inhibition and G2/M cell cycle arrest in rat tendon cells. Arthritis Rheum. 2008 Jun;58(6):1657-63.

[2]. In Vitro and In Vivo Activity of Omadacycline against Two Biothreat Pathogens, Bacillus anthracis and Yersinia pestis. Antimicrob Agents Chemother. 2017 Apr 24;61(5):e02434-16.

[3]. Inhaled Liposomal Ciprofloxacin Protects against a Lethal Infection in a Murine Model of Pneumonic Plague. Front Microbiol. 2017 Feb 6;8:91.

[4]. Effect of Ciprofloxacin on Susceptibility to Aortic Dissection and Rupture in Mice. JAMA Surg. 2018 Sep 1;153(9):e181804.

Therapeutic Uses
Anti-Infective Agents; Nucleic Acid Synthesis Inhibitors
Ciprofloxacin (IV, conventional tablets, oral suspension) is used in adults for the treatment of bone and joint infections, including osteomyelitis, caused by susceptible E. cloacae, ... Ps. aeruginosa, or S. marcescens. ... /Included in US product label/
Ciprofloxacin (IV, conventional tablets, oral suspension) is used in adults for the treatment of bone and joint infections, including osteomyelitis, caused by susceptible E. aerogenes, ... E. coli, K. pneumoniae, M. morganii, P. mirabilis, ... . The drug also has been used in adults for the treatment of bone and joint infections caused by susceptible S. aureus, S. epidermidis, other coagulase-negative staphylococci, or Enterococcus faecalis (formerly S. faecalis), but other anti-infectives generally are preferred for these infections. Although resistance to ciprofloxacin has been reported in some strains of oxacillin-resistant S. aureus, oral ciprofloxacin may be a useful alternative to parenteral anti-infectives for the treatment of infections caused by susceptible oxacillin-resistant staphylococci. /NOT included in US product label/
Although only limited experience is available to date, ciprofloxacin is recommended by the American Heart Association (AHA) and Infectious Diseases Society of America (IDSA) as an alternative agent for the treatment of native or prosthetic valve endocarditis caused by fastidious gram-negative bacilli known as the HACEK group (Actinobacillus actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens, Haemophilus aphrophilus, H. influenzae, H. parainfluenzae, H. paraphrophilus, Kingella denitrificans, K. kingae). /NOT included in US product label/
For more Therapeutic Uses (Complete) data for CIPROFLOXACIN (53 total), please visit the HSDB record page.

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Drug Warnings
/BOXED WARNING/ WARNING: Fluoroquinolones, including Cipro, 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.
/BOXED WARNING/ WARNING: Fluoroquinolones, including Cipro, may exacerbate muscle weakness in persons with myasthenia gravis. Avoid Cipro in patients with known history of myasthenia gravis.
In 4 corneal transplantation patients treated preoperatively with ciprofloxacin ophthalmic drops, microprecipitates associated with damaged corneal epithelium were noted in 2 patients. Another patient developed a large macroprecipitate in a corneal ulcer. All specimens were examined by electron microscopy & high-pressure liquid chromatography. The crystalline precipitates were pure ciprofloxacin. The macroprecipitate demonstrated a large zone of inhibition on agar plates seeded with a susceptible organism at 24 & 48 hr. It was bioactive & bioavailable in vitro.
Serious and occasionally fatal hypersensitivity (anaphylactic) reactions, some following the first dose, have been reported in patients receiving quinolone therapy. 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. Serious anaphylactic reactions require immediate emergency treatment with epinephrine. Oxygen, intravenous steroids, and airway management, including intubation, should be administered as indicated.
For more Drug Warnings (Complete) data for CIPROFLOXACIN (41 total), please visit the HSDB record page.

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Pharmacodynamics
Ciprofloxacin is a second generation fluoroquinolone that is active against many Gram negative and Gram positive bacteria. It produces its action through inhibition of bacterial DNA gyrase and topoisomerase IV. Ciprofloxacin binds to bacterial DNA gyrase with 100 times the affinity of mammalian DNA gyrase. There is no cross resistance between fluoroquinolones and other classes of antibiotics, so it may be of clinical value when other antibiotics are no longer effective. Ciprofloxain and its derivatives are also being investigated for its action against malaria, cancers, and AIDS.

C17H18FN3O3

331.34

331.133

C, 61.62; H, 5.48; F, 5.73; N, 12.68; O, 14.49

85721-33-1

86393-32-0;93107-08-5;97867-33-9

2764

White to off-white solid powder

1.5±0.1 g/cm3

581.8±50.0 °C at 760 mmHg

255-257°C

305.6±30.1 °C

0.0±1.7 mmHg at 25°C

1.655

0.65

2

7

3

24

571

0

O=C(C1C(=O)C2C(=CC(N3CCNCC3)=C(C=2)F)N(C2CC2)C=1)O

MYSWGUAQZAJSOK-UHFFFAOYSA-N

InChI=1S/C17H18FN3O3/c18-13-7-11-14(8-15(13)20-5-3-19-4-6-20)21(10-1-2-10)9-12(16(11)22)17(23)24/h7-10,19H,1-6H2,(H,23,24)

1-cyclopropyl-6-fluoro-4-oxo-7-piperazin-1-ylquinoline-3-carboxylic acid

2934.99.03.00

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: This product requires protection from light (avoid light exposure) during transportation and storage.

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

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.)