TOPO IV

Absorption, Distribution and Excretion
The bioavailability of ofloxacin tablets is approximately 98%. Ofloxacin is primarily eliminated through renal excretion. After oral administration, 65% to 80% of the dose is excreted unchanged in the urine within 48 hours. Approximately 4-8% of the ofloxacin dose is excreted in feces, with very little excretion in bile. Ofloxacin is distributed in bones, cartilage, bile, skin, sputum, bronchial secretions, pleural effusion, tonsils, saliva, gingival mucosa, nasal secretions, aqueous humor, tears, sweat, lungs, vesicular fluid, pancreatic juice, ascites, peritoneal fluid, gynecological tissues, vaginal fluid, cervix, ovaries, semen, prostatic fluid, and prostatic tissue. In most of these tissues and fluids, the concentration of ofloxacin is approximately 0.5-1.7 times the corresponding serum concentration. Ofloxacin primarily accumulates within neutrophils, with intracellular concentrations up to eight times higher than extracellular concentrations. After oral administration, ofloxacin is widely distributed throughout the body's tissues and fluids. In healthy adults, the apparent volume of distribution (VOD) of ofloxacin is on average 1–2.5 L/kg. Renal impairment does not appear to affect the VOD of ofloxacin; in patients with impaired renal function, including those with severe renal failure undergoing hemodialysis, the apparent VOD is on average 1.1–2 L/kg. Pharmacokinetic parameters of ofloxacin in elderly patients are generally similar to those in younger adults. Although pharmacokinetic studies in elderly individuals aged 65–81 years showed similar absorption rates, VODs, and excretion pathways compared to younger adults, older patients exhibited slightly higher peak serum concentrations (9–21% higher) and longer half-lives. Furthermore, there is evidence that older women have higher peak plasma concentrations than older men (114% higher after a single dose and 54% higher after multiple doses).
The bioavailability of ofloxacin via oral administration in healthy, fasting adults is 85-100%, with peak serum concentrations typically reached within 0.5-2 hours. In patients with normal renal and hepatic function, peak serum concentrations and AUC increase with increasing dose within the oral dose range of 100-600 mg, and are generally unaffected by age. The mean peak serum concentrations following a single oral dose of 100, 200, 300, or 400 mg of ofloxacin in healthy, fasting adults are 1-1.3, 1.5-2.7, 2.4-4.6, or 2.9-5.6 μg/mL, respectively. Drug accumulation may occur after multiple administrations. Steady-state serum concentrations of ofloxacin are reached after four administrations, approximately 40% higher than the concentration following a single oral dose.
For more complete data on the absorption, distribution, and excretion of ofloxacin (18 items in total), please visit the HSDB record page.

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Metabolism/Metabolites
Hepatic Metabolism
After a single dose of ofloxacin, less than 10% is metabolized; approximately 3-6% is metabolized to desmethylofloxacin, and 1-5% to ofloxacin N-oxide. Desmethylofloxacin has microbial activity, but its activity against susceptible bacteria is lower than that of ofloxacin; ofloxacin N-oxide has only very low antibacterial activity.
Seven patients with end-stage renal disease undergoing regular hemodialysis received oral ofloxacin treatment with an initial loading dose of 200 mg, followed by multiple daily maintenance doses of 100 mg for 10 days. At the end of treatment, the pharmacokinetics of ofloxacin and its metabolites were studied. The concentrations of ofloxacin and its metabolites in plasma and dialysate were determined by high-performance liquid chromatography (HPLC). The peak concentration (3.1 mg·L⁻¹), trough concentration (1.6 mg·L⁻¹), and AUC of ofloxacin were comparable to those after oral administration of 300 to 400 mg of ofloxacin in healthy volunteers. The mean half-lives measured during the non-dialysis interval (t₁/₂β) and during hemodialysis (t₁/₂HD) were 38.5 hours and 9.9 hours, respectively. Extrarenal clearance (32.7 mL·min⁻¹) was unchanged compared to that after a single dose of ofloxacin in healthy volunteers. Hemodialysis clearance was 21.5%. Two metabolites, ofloxacin-N-oxide and desmethylofloxacin, were detected in plasma. Despite prolonged half-lives (t1/2β) for both metabolites (66.1 hours and 50.9 hours, respectively) and multiple doses of ofloxacin, the peak concentrations of the metabolites were only 14% and 5% of the parent drug, respectively. The conclusion is that the dose adjustment regimen used achieves safe and therapeutically significant plasma concentrations in patients receiving regular hemodialysis. The observed accumulation of ofloxacin metabolites appears to have no toxic or therapeutic significance.
Biological Half-Life
9 hours
In adults with creatinine clearance of 10–50 mL/min, the mean half-life of this drug is 16.4 hours (range: 11–33.5 hours); in adults with creatinine clearance less than 10 mL/min, the mean half-life is 21.7 hours (range: 16.9–28.4 hours). In patients with end-stage renal failure, the half-life of this drug may be 25–48 hours.
In healthy adults with normal renal function, the mean elimination half-life of ofloxacin in the distribution phase is 0.5–0.6 hours, and the mean elimination half-life in the terminal phase is 4–8 hours. In healthy elderly individuals aged 64-86 years with normal renal function, the mean half-life of this drug is 6.4-8.5 hours. In healthy subjects, with one drop of 0.3% ofloxacin eye drops four times daily for a total of 12 days, the elimination half-life of the drug in the tear film was approximately 226 minutes. In a rabbit study, the terminal elimination half-life of ofloxacin in the tear film after topical instillation was approximately 210 minutes. For adults with normal renal function, the mean serum elimination half-life of ofloxacin in the terminal phase is 4-8 hours.

Hepatotoxicity
In patients taking ofloxacin, 1% to 2% may experience mild elevations in ALT and alkaline phosphatase levels. These abnormalities are usually mild, asymptomatic, and transient, resolving spontaneously with continued treatment. Ofloxacin is also associated with rare but occasionally severe and even fatal cases of acute liver injury. Onset is usually short (2 days to 2 weeks), with symptoms often appearing suddenly, including nausea, fatigue, abdominal pain, and jaundice. The pattern of serum enzyme elevation can be hepatocellular or cholestatic; cases with shorter onset are usually more hepatocellular, with significantly elevated ALT levels, sometimes accompanied by a rapidly prolonged prothrombin time and signs of liver failure. Symptoms may appear within days of discontinuation of the drug. Cases with cholestatic enzyme elevations may have a longer course but usually resolve spontaneously. Many (but not all) cases present with allergic reactions, including fever, rash, and eosinophilia. Autoantibodies are usually not present. The hepatotoxicity of ofloxacin is similar to that of other fluoroquinolones, seemingly representing a common effect of this class of drugs.
Probability Score: A (Established but rare clinically significant cause of liver injury).

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Pregnancy and Lactation Effects
◉ Overview of Lactation Use
Ofloxacin can be found in small amounts in breast milk. Fluoroquinolones are traditionally not used to treat infants due to concerns about adverse effects on developing joints. However, recent studies suggest the risk is minimal. Calcium in breast milk may prevent the absorption of small amounts of fluoroquinolones in breast milk. There is currently insufficient data to confirm or refute this claim. Two infants have been reported to have developmental problems due to the presence of ofloxacin in their breast milk, but their mothers were also exposed to multiple medications during pregnancy and lactation, so these problems are not necessarily attributable to ofloxacin. Use of ofloxacin by breastfeeding mothers is acceptable, but close monitoring of the infant's gut microbiota is necessary, for example, for changes in diarrhea or candidiasis (thrush, diaper rash). Avoiding breastfeeding for 4 to 6 hours after medication can reduce the risk of the infant being exposed to ofloxacin through breast milk. The risk to a breastfeeding infant from the mother using ear drops or eye drops containing ofloxacin is negligible. To significantly reduce the amount of medication that enters breast milk after using eye drops, press on the tear duct near the corner of the eye for at least 1 minute, then wipe away any excess medication with absorbent tissue.
◉ Effects on Breastfed Infants
Ofloxacin was used as part of a multidrug regimen to treat two pregnant women with multidrug-resistant tuberculosis; one woman used it throughout pregnancy and postpartum, while the other used it only postpartum. Both infants were breastfed (the extent and duration of breastfeeding were not specified). Both children were developmentally normal at 4.6 and 5.1 years of age, respectively; one child had mild language delay, and the other had ADHD.
◉ Effects on Breastfeeding and Breast Milk
No published information was found as of the revision date.

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Protein Binding Rate
32%Drug Interactions
In patients receiving theophylline, concomitant use of certain fluoroquinolone anti-infective drugs (e.g., ciprofloxacin, norfloxacin, ofloxacin) can lead to elevated serum theophylline concentrations and prolonged duration of action, potentially increasing the risk of theophylline-related adverse reactions. The extent of this interaction varies considerably among commercially available fluoroquinolones; norfloxacin or ofloxacin have a smaller effect compared to ciprofloxacin. While studies have shown that the 4-oxotransferases of these quinolones may inhibit theophylline metabolism in the liver, and there is evidence that the extent to which different quinolones are metabolized into 4-oxotransferases may be correlated with the degree of theophylline pharmacokinetics alteration when these drugs are used in combination, the potential contribution (if any) of 4-oxotransferases to this interaction has not been fully elucidated. Furthermore, other evidence suggests that while the formation of these metabolites may be associated with the inhibition of theophylline metabolism, the 4-oxotransferases themselves are not the cause of the observed effects. Studies using other fluoroquinolones (such as ciprofloxacin) have shown that concomitant use of probenecid can interfere with the renal tubular secretion of these drugs. The effects of combining probenecid with ofloxacin have not yet been studied. It has been reported that concomitant use of fluoroquinolones (such as ofloxacin) with fenbufen (a nonsteroidal anti-inflammatory drug (NSAIA)) can lead to an increased incidence of seizures. Concomitant use of fluoroquinolones with NSAIAs may increase the risk of central nervous system excitation (such as seizures). Animal studies using other fluoroquinolones suggest that the risk may vary depending on the specific NSAIA. Oral multivitamin and mineral supplements containing divalent or trivalent cations (such as iron or zinc) may reduce the oral absorption of ofloxacin, thereby reducing serum concentrations of quinolones; therefore, these multivitamin and/or mineral supplements should not be taken concurrently with or within 2 hours of taking ofloxacin. In a crossover study, concurrent oral administration of a single dose of ferrous sulfate complex and ofloxacin reduced the AUC of the anti-infective drug by 36%. For more complete data on interactions of ofloxacin (out of 19), please visit the HSDB record page. Non-human toxicity values: Rat intravenous LD50 273 mg/kg; Rat subcutaneous LD50 7070 mg/kg; Rat oral LD50 3590 mg/kg; Monkey oral LD50 500 mg/kg. For more complete data on non-human toxicity values of ofloxacin (out of 6), please visit the HSDB record page.

[1]. Effect of levofloxacin on neutrophilic airway inflammation in stable COPD: a randomized, double-blind, placebo-controlled trial. Int J Chron Obstruct Pulmon Dis, 2014. 9: p. 179-86.

[2]. Clinical and microbiological effects of levofloxacin in the treatment of chronic periodontitis: a randomized, placebo-controlled clinical trial. J Investig Clin Dent, 2014.

[3]. Efficacy of Levofloxacin in the Treatment of BK Viremia: A Multicenter, Double-Blinded, Randomized, Placebo-Controlled Trial. Clin J Am Soc Nephrol, 2014.

[4]. Drugs.1994 Apr;47(4):677-700.

[5]. Antimicrob Agents Chemother.1992 Apr;36(4):860-6.

Therapeutic Uses

Antimicrobial; Anti-infective, urinary tract; Nucleic acid synthesis inhibitor
Ofloxacin is used to treat acute pelvic inflammatory disease (PID) caused by susceptible Chlamydia trachomatis or Neisseria gonorrhoeae, but should not be used if QRNG may be involved or in vitro susceptibility testing is not possible. /US product label includes/
Ofloxacin is used to treat non-gonococcal urethritis and cervicitis in adults caused by Chlamydia trachomatis. /US product label includes/
Ofloxacin is used to treat uncomplicated urinary tract infections (cystitis) in adults caused by susceptible Gram-negative bacteria, including Citrobacter, Enterobacter aerogenes, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, or Pseudomonas aeruginosa. /US product label includes/
For more complete data on the therapeutic uses of ofloxacin (36 types), please visit the HSDB record page.

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Drug Warning
/Black Box Warning/ Warning: Fluoroquinolones, including ofloxacin, are associated with an increased risk of tendinitis and tendon rupture in all age groups. This risk is further increased in older patients (typically over 60 years of age), patients taking corticosteroids, and patients who have received kidney, heart, or lung transplants.
/Black Box Warning/ Warning: Fluoroquinolones (including ofloxacin) may worsen muscle weakness symptoms in patients with myasthenia gravis. Ofloxacin should be avoided in patients with a known history of myasthenia gravis.
Certain quinolones (including ofloxacin) have been associated with QT interval prolongation and rare cases of arrhythmias on electrocardiograms. Rare cases of torsades de pointes ventricular tachycardia have been spontaneously reported in patients treated with quinolones (including ofloxacin) during postmarketing surveillance. Rare cases of sensory or sensorimotor axonal polyneuropathy have been reported in patients treated with quinolone antibiotics, including ofloxacin. These cases affect small and/or large axons, leading to paresthesia, hypoesthesia, sensory disturbances, and muscle weakness. Ofloxacin should be discontinued if a patient develops neuropathy symptoms, including pain, burning, tingling, numbness, and/or muscle weakness, or other sensory changes, including light touch, pain, temperature, position, and vibration sensation, to prevent the development of irreversible disease. For more complete data on drug warnings for ofloxacin (28 in total), please visit the HSDB records page.

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Pharmacodynamics
Ofloxacin is a quinolone/fluoroquinolone antibiotic. Ofloxacin is a bactericidal agent that works by binding to an enzyme called DNA gyrase, which blocks bacterial DNA replication. DNA gyrase unwinds the DNA double helix, thus preventing DNA replication into two double helices. It is worth noting that this drug has a 100-fold higher affinity for bacterial DNA gyrase than for mammalian DNA gyrase. Ofloxacin is a broad-spectrum antibiotic effective against both Gram-positive and Gram-negative bacteria.

C36H42F2N6O9

740.76

740.2981

C, 58.37; H, 5.72; F, 5.13; N, 11.35; O, 19.44

138199-71-0

Levofloxacin;100986-85-4;Levofloxacin hydrochloride;177325-13-2;(R)-Ofloxacin;100986-86-5

4583

White to off-white solid powder

1.48g/cm3

571.5ºC at 760mmHg

214-216°C

6.7E-14mmHg at 25°C

1.482

1

8

2

26

634

0

FC1C([H])=C2C(C(C(=O)O[H])=C([H])N3C2=C(C=1N1C([H])([H])C([H])([H])N(C([H])([H])[H])C([H])([H])C1([H])[H])OC([H])([H])C3([H])C([H])([H])[H])=O

SUIQUYDRLGGZOL-RCWTXCDDSA-N

InChI=1S/2C18H20FN3O4.H2O/c2*1-10-9-26-17-14-11(16(23)12(18(24)25)8-22(10)14)7-13(19)15(17)21-5-3-20(2)4-6-21;/h2*7-8,10H,3-6,9H2,1-2H3,(H,24,25);1H2/t2*10-;/m00./s1

(S)-9-Fluoro-3-methyl-10-(4-methylpiperazin-1-yl)-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylic acid hemihydrate

RWJ 25213; RWJ-25213; RWJ25213; Levofloxacin Hydrate; Levofloxacin Hemihydrate

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)

H2O : ≥ 50 mg/mL (~135.00 mM)
Ethanol : ~10 mg/mL
DMSO : ~8.33 mg/mL (~22.49 mM)

Solubility in Formulation 1: ≥ 0.83 mg/mL (2.24 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 8.3 mg/mL clear DMSO stock solution to 400 μL of PEG300 and mix evenly; then add 50 μL of Tween-80 to the above solution and mix evenly; then add 450 μL of 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.

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Solubility in Formulation 2: ≥ 0.83 mg/mL (2.24 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in 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 8.3 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
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.

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Solubility in Formulation 3: ≥ 0.83 mg/mL (2.24 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 8.3 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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Solubility in Formulation 4: 10% DMSO+40% PEG300+5% Tween-80+45% Saline: ≥ 0.83 mg/mL (2.24 mM)

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Solubility in Formulation 5: 100 mg/mL (269.99 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication.

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