TOPO IV

Absorption, Distribution and Excretion
Bioavailability of ofloxacin in the tablet formulation is approximately 98%
Ofloxacin is mainly eliminated by renal excretion, where between 65% and 80% of an administered oral dose of ofloxacin is excreted unchanged via urine within 48 hours of dosing. About 4-8% of an ofloxacin dose is excreted in the feces and the drug is minimally subject to biliary excretion.
Ofloxacin is distributed into bone, cartilage, bile, skin, sputum, bronchial secretions, pleural effusions, tonsils, saliva, gingival mucosa, nasal secretions, aqueous humor, tears, sweat, lung, blister fluid, pancreatic fluid, ascitic fluid, peritoneal fluid, gynecologic tissue, vaginal fluid, cervix, ovary, semen, prostatic fluid, and prostatic tissue. For most of these tissues and fluids, ofloxacin concentrations are approximately 0.5-1.7 times concurrent serum concentrations. Ofloxacin is concentrated within neutrophils, achieving concentrations in these cells that may be up to 8 times greater than extracellular concentrations.
Ofloxacin is widely distributed into body tissues and fluids following oral administration. In healthy adults, the apparent volume of distribution of ofloxacin averages 1-2.5 L/kg. Impaired renal function does not appear to affect the volume of distribution of ofloxacin; the apparent volume of distribution of the drug averages 1.1-2 L/kg in patients with impaired renal function, including those with severe renal failure undergoing hemodialysis.
Pharmacokinetic parameters in geriatric patients receiving ofloxacin generally are similar to those in younger adults. Although results of pharmacokinetic studies in geriatric individuals 65-81 years of age indicate that the rate of absorption, volume of distribution, and route of excretion in geriatric individuals are similar to those in younger adults, peak serum concentrations are slightly higher (9-21% higher) and half-life more prolonged in geriatric patients than in younger adults. There also is evidence that peak plasma concentration are higher in geriatric women than geriatric men (114% higher following single doses or 54% higher following multiple doses).
The oral bioavailability of ofloxacin is 85-100% in healthy, fasting adults, and peak serum concentrations of the drug generally are attained within 0.5-2 hours. In patients with normal renal and hepatic function, peak serum concentrations and AUCs increase in proportion to the dose over the oral dosage range of 100-600 mg and generally are unaffected by age. Following oral administration of a single 100-, 200-, 300-, or 400-mg dose of ofloxacin in healthy, fasting adults, peak serum concentrations average 1-1.3, 1.5-2.7, 2.4-4.6, or 2.9-5.6 ug/mL, respectively. Some accumulation occurs following multiple doses. Steady-state serum concentrations of ofloxacin are achieved after 4 doses of the drug and are approximately 40% higher than concentrations achieved following single oral doses.
For more Absorption, Distribution and Excretion (Complete) data for Ofloxacin (18 total), please visit the HSDB record page.

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Metabolism / Metabolites
Hepatic
Less than 10% of a single dose of ofloxacin is metabolized; approximately 3-6% of the dose is metabolized to desmethyl ofloxacin and 1-5% is metabolized to ofloxacin N-oxide. Desmethyl ofloxacin is microbiologically active, but is less active against susceptible organisms than is ofloxacin; ofloxacin N-oxide has only minimal antibacterial activity.
Seven patients with end-stage renal disease on regular hemodialysis were treated orally with a loading dose of 200 mg ofloxacin and multiple maintenance doses of 100 mg per 24 hr for 10 days. The pharmacokinetics of ofloxacin and its metabolites were studied at the end of the treatment period. Plasma and dialysate concentrations of ofloxacin and ofloxacin metabolites were measured by HPLC. Peak (3.1 mg.L-1) and trough levels (1.6 mg.L-1) and the AUC of ofloxacin were comparable to the values in healthy volunteers given 300 to 400 mg ofloxacin p.o. The mean half-life, determined in the dialysis-free interval (t1/2 beta) and during the haemodialysis session (t1/2 HD), was 38.5 h and 9.9 h, respectively. Extrarenal clearance (32.7 mL.min-1) was unchanged as compared to that reported in healthy volunteers after a single dose of ofloxacin. The fractional removal by haemodialysis amounted to 21.5%. Two metabolites, ofloxacin-N-oxide and demethyl-ofloxacin, were detected in plasma. Despite prolonged t1/2 beta of both metabolites (66.1 and 50.9 hr) and multiple doses of ofloxacin the peak concentrations of the metabolites reached only 14% and 5% of that of the parent drug, respectively. It is concluded that in patients on regular hemodialysis treatment the dosage adjustment employed resulted in safe and therapeutically favourable plasma concentrations. The observed accumulation of ofloxacin metabolites does not appear to have any toxic or therapeutic significance.

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Biological Half-Life
9 hours
In adults with creatinine clearances of 10-50 mL/minute, half-life of the drug averages 16.4 hours (range: 11-33.5 hours); in adults with creatinine clearances less than 10 mL/minute, half-life averages 21.7 hours (range: 16.9-28.4 hours). In patients with end-stage renal failure, half-life of the drug may range from 25-48 hours.
In healthy adults with normal renal function, the elimination half-life of ofloxacin in the distribution phase averages 0.5-0.6 hours and the elimination half-life in the terminal phase averages 4-8 hours.In healthy geriatric adults 64-86 years of age with renal function normal for their age, half-life of the drug averages 6.4-8.5 hours.
Following ocular instillation of 1 drop of ofloxacin 0.3% 4 times daily for 12 doses in healthy individuals, the elimination half-life of drug in tear film was approximately 226 minutes. In a study in rabbits, the terminal elimination half-life of ofloxacin in tear film following topical application to the eye was approximately 210 minutes. In adults with normal renal function, the serum elimination half-life of ofloxacin in the terminal phase averages 4-8 hours.

Hepatotoxicity
Mild elevations in ALT and alkaline phosphatase levels occur in 1 to 2% of patients on ofloxacin. These abnormalities are generally mild, asymptomatic and transient, resolving even with continuation of therapy. Ofloxacin has also been linked to rare but occasionally severe and even fatal cases of acute liver injury. The time to onset is typically short (2 days to 2 weeks) and the presentation is often abrupt with nausea, fatigue, abdominal pain and jaundice. 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. Cases with a cholestatic pattern of enzymes may run a prolonged course but are usually self-limiting. Many (but not all) cases have had allergic manifestations with fever, rash and eosinophilia. Autoantibodies are usually not present. The hepatotoxicity of ofloxacin is similar to that of other fluoroquinolones and appears to represent a class effect.
Likelihood score: A (well established but rare cause of clinically apparent liver injury).

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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Ofloxacin appears in breastmilk in low levels. Fluoroquinolones have traditionally not been used in infants because of concern about adverse effects on the infants' developing joints. However, recent studies indicate little risk. The calcium in milk might prevent absorption of the small amounts of fluoroquinolones in milk. Insufficient data exist to prove or disprove this assertion. Developmental problems have been reported in two infants exposed to ofloxacin in breastmilk, but their mothers were also exposed to several drugs during pregnancy and during breastfeeding, so the problems cannot necessarily be attributed to ofloxacin. Use of ofloxacin is acceptable in nursing mothers with monitoring of the infant for possible effects on the flora, such as diarrhea or candidiasis (thrush, diaper rash). . Avoiding breastfeeding for 4 to 6 hours after a dose should decrease the exposure of the infant to ofloxacin in breastmilk.
Maternal use of an ear drop or eye drop that contains ofloxacin presents negligible risk for the nursing infant. To substantially diminish the amount of drug that reaches the breastmilk after using eye drops, place pressure over the tear duct by the corner of the eye for 1 minute or more, then remove the excess solution with an absorbent tissue.
◉ Effects in Breastfed Infants
Ofloxacin was used as part of multidrug regimens to treat two pregnant women with multidrug-resistant tuberculosis, one throughout pregnancy and postpartum and the other postpartum only. The infants were breastfed (extent and duration not stated). At age 4.6 and 5.1 years, the children were developing normally except for a mild speech delay in one and hyperactivity in the other.
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.

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Protein Binding
32%

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Interactions
Concomitant administration of some fluoroquinolone anti-infectives (e.g., ciprofloxacin, norfloxacin, ofloxacin) in patients receiving theophylline has resulted in higher and prolonged serum theophylline concentrations and may increase the risk of theophylline-related adverse effects. The extent of this interaction varies considerably among the commercially available fluoroquinolones; the effect is less pronounced with norfloxacin or ofloxacin than with ciprofloxacin. While it has been suggested that the 4-oxo metabolites of these quinolones may inhibit metabolism of theophylline in the liver, and there is some evidence that the degree to which the various quinolones are metabolized to 4-oxo metabolites may correlate with the extent of alteration in theophylline pharmacokinetics when the drugs are administered concomitantly, the potential contribution, if any, of the 4-oxo metabolites to this interaction has not been fully elucidated. In addition, other evidence indicates that, while formation of these metabolites may correlate with inhibition of theophylline metabolism, the 4-oxo metabolites themselves are not responsible for the observed effect.
Studies using other fluoroquinolones (e.g., ciprofloxacin) indicate that concomitant administration of probenecid interferes with renal tubular secretion of the drugs. The effect of concomitant administration of probenecid and ofloxacin has not been studied to date.
Concomitant administration of a fluoroquinolone (i.e., ofloxacin) and fenbufen (a nonsteroidal anti-inflammatory agent (NSAIA)) reportedly resulted in an increased incidence of seizures. Concomitant use of a fluoroquinolone with an NSAIA could increase the risk of CNS stimulation (e.g., 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 decrease oral absorption of ofloxacin resulting in decreased serum concentrations of the quinolone; therefore, these multivitamins and/or mineral supplements should not be ingested concomitantly with or within 2 hours of an ofloxacin dose. In a crossover study, concomitant administration of a single dose of oral ferrous sulfate complex and ofloxacin decreased the AUC of the anti-infective by 36%.
For more Interactions (Complete) data for Ofloxacin (19 total), please visit the HSDB record page.

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Non-Human Toxicity Values
LD50 Rat iv 273 mg/kg
LD50 Rat sc 7070 mg/kg
LD50 Rat oral 3590 mg/kg
LD50 Monkey oral 500 mg/kg
For more Non-Human Toxicity Values (Complete) data for Ofloxacin (6 total), 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
Anti-Bacterial Agents; Anti-Infective Agents, Urinary; Nucleic Acid Synthesis Inhibitors
Ofloxacin is used in the treatment of acute pelvic inflammatory disease (PID) caused by susceptible C. trachomatis or N. gonorrhoeae, but should not be used if QRNG may be involved or if in vitro susceptibility cannot be tested. /Included in US product label/
Ofloxacin is used in adults for the treatment of nongonococcal urethritis and cervicitis caused by Chlamydia trachomatis. /Included in US product label/
Ofloxacin is used in adults for the treatment of uncomplicated urinary tract infections (UTIs) (cystitis) caused by susceptible gram-negative bacteria, including Citrobacter diversus, ... Enterobacter aerogenes, ... Escherichia coli, Klebsiella pneumoniae, ... Proteus mirabilis, or Pseudomonas aeruginosa. /Included in US product label/
For more Therapeutic Uses (Complete) data for Ofloxacin (36 total), please visit the HSDB record page.

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Drug Warnings
/BOXED WARNING/ WARNING: Fluoroquinolones, including ofloxacin, 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 ofloxacin, may exacerbate muscle weakness in persons with myasthenia gravis. Avoid ofloxacin in patients with known history of myasthenia gravis.
Some quinolones, including ofloxacin, have been associated with prolongation of the QT interval on the electrocardiogram and infrequent cases of arrhythmia. Rare cases of torsade de pointes have been spontaneously reported during postmarketing surveillance in patients receiving quinolones, including ofloxacin.
Rare cases of sensory or sensorimotor axonal polyneuropathy affecting small and/or large axons resulting in paresthesias, hypoesthesias, dysesthesias and weakness have been reported in patients receiving quinolones, including ofloxacin. Ofloxacin should be discontinued if the patient experiences symptoms of neuropathy including pain, burning, tingling, numbness, and/or weakness or other alterations of sensation including light touch, pain, temperature, position sense, and vibratory sensation in order to prevent the development of an irreversible condition.
For more Drug Warnings (Complete) data for Ofloxacin (28 total), please visit the HSDB record page.

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Pharmacodynamics
Ofloxacin is a quinolone/fluoroquinolone antibiotic. Ofloxacin 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. Ofloxacin is a broad-spectrum antibiotic that is active 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.)