Ofloxacin (Hoe-280; DL8280)   中文名称: 氧氟沙星

Topo II; Topoisomerase IV

氧氟沙星 (Hoe-280) 是一种氟喹诺酮类药物，主要通过抑制称为 DNA 旋转酶的细菌酶发挥作用。虽然它对厌氧菌的作用不那么有效，但它在体外对需氧革兰氏阴性和革兰氏阳性细菌表现出广泛的活性[1]。与其他 4-喹诺酮类药物一样，氧氟沙星 (Hoe-280) 在治疗细菌感染的一线药物中是独一无二的，因为它影响细菌 DNA 的合成，而不是细胞壁或蛋白质 [2]。

氧氟沙星 (Hoe-280) (20 mg/kg)、诺氟沙星 (40 mg/kg)、甲磺酸培氟沙星二水合物 (40 mg/kg) 和环丙沙星 (50 mg/kg) 每天两次灌胃，连续三周。治疗六周后，让试验动物入睡，并采集跟腱样本。使用计算机监控的拉伸测试设备进行生物力学测试。对照组的平均弹性模量显着高于诺氟沙星组和培氟沙星组（分别为p<0.05和p<0.01）。与用环丙沙星、诺氟沙星和培氟沙星治疗的组相比，对照组表现出显着更高的平均屈服力（YF）（分别为p<0.001、p<0.05和p<0.01）。与环丙沙星、诺氟沙星和培氟沙星组相比，对照组的平均极限拉力（UTF）显着更高（分别为p<0.001、p<0.05和p<0.01）。在环丙沙星、培氟沙星和氧氟沙星治疗组的肌腱中，观察到透明变性和纤维紊乱，但仅在环丙沙星和培氟沙星组中出现粘液瘤变性[3]。

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]. Ofloxacin. A reappraisal of its antimicrobial activity, pharmacology and therapeutic use. Drugs. 1991 Nov;42(5):825-76.

[2]. Ofloxacin, a bactericidal antibacterial. Chemotherapy. 1991;37 Suppl 1:2-13.

[3]. Oral toxicity of pefloxacin, norfloxacin, ofloxacin and ciprofloxacin: comparison of biomechanical and histopathological effects on Achilles tendon in rats. J Toxicol Sci. 2011 Jun;36(3):339-45.

[4]. Antiviral activity and inhibition of topoisomerase by ofloxacin, a new quinolone derivative. Antiviral Res. 1987 Oct;8(3):103-13.

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.

C18H20FN3O4

361.37

361.143

C, 59.83; H, 5.58; F, 5.26; N, 11.63; O, 17.71

82419-36-1

4583

Off-white to light yellow crystalline powder

1.5±0.1 g/cm3

571.5±50.0 °C at 760 mmHg

270-2750C

299.4±30.1 °C

0.0±1.7 mmHg at 25°C

1.670

0.84

75.01

1

8

2

26

634

0

O=C(C1C(=O)C2C3=C(C(N4CCN(C)CC4)=C(C=2)F)OCC(N3C=1)C)O

GSDSWSVVBLHKDQ-UHFFFAOYSA-N

InChI=1S/C18H20FN3O4/c1-10-9-26-17-14-11(16(23)12(18(24)25)8-22(10)14)7-13(19)15(17)21-5-3-20(2)4-6-21/h7-8,10H,3-6,9H2,1-2H3,(H,24,25)

7-fluoro-2-methyl-6-(4-methylpiperazin-1-yl)-10-oxo-4-oxa-1-azatricyclo[7.3.1.05,13]trideca-5(13),6,8,11-tetraene-11-carboxylic acid

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)

注意: 如下所列的是一些常用的体内动物实验溶解配方，主要用于溶解难溶或不溶于水的产品（水溶度<1 mg/mL）。 建议您先取少量样品进行尝试，如该配方可行，再根据实验需求增加样品量。

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注射用配方1: DMSO : Tween 80： Saline = 10 : 5 : 85 (如： 100 μL DMSO → 50 μL Tween 80 → 850 μL Saline)
*生理盐水/Saline的制备：将0.9g氯化钠/NaCl溶解在100 mL ddH ₂ O中，得到澄清溶液。
注射用配方 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (如： 100 μL DMSO → 400 μL PEG300 → 50 μL Tween 80 → 450 μL Saline)
注射用配方 3: DMSO : Corn oil = 10 : 90 (如： 100 μL DMSO → 900 μL Corn oil)
示例: 以注射用配方 3 (DMSO : Corn oil = 10 : 90) 为例说明, 如果要配制 1 mL 2.5 mg/mL的工作液, 您可以取 100 μL 25 mg/mL 澄清的 DMSO 储备液，加到 900 μL Corn oil/玉米油中, 混合均匀。

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注射用配方 4: DMSO : 20% SBE-β-CD in Saline = 10 : 90 [如：100 μL DMSO → 900 μL (20% SBE-β-CD in Saline)]
*20% SBE-β-CD in Saline的制备（4°C，储存1周）：将2g SBE-β-CD (磺丁基-β-环糊精) 溶解于10mL生理盐水中，得到澄清溶液。
注射用配方 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (如： 500 μL 2-Hydroxypropyl-β-cyclodextrin (羟丙基环胡精)→ 500 μL Saline)
注射用配方 6: DMSO : PEG300 : Castor oil : Saline = 5 : 10 : 20 : 65 (如： 50 μL DMSO → 100 μL PEG300 → 200 μL Castor oil → 650 μL Saline)
注射用配方 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (如： 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
注射用配方 8: 溶解于Cremophor/Ethanol (50 : 50), 然后用生理盐水稀释。
注射用配方 9: EtOH : Corn oil = 10 : 90 (如： 100 μL EtOH → 900 μL Corn oil)
注射用配方 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (如： 100 μL EtOH → 400 μL PEG300 → 50 μL Tween 80 → 450 μL Saline)

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口服配方 1: 悬浮于0.5% CMC Na (羧甲基纤维素钠)
口服配方 2: 悬浮于0.5% Carboxymethyl cellulose (羧甲基纤维素)
示例: 以口服配方 1 (悬浮于 0.5% CMC Na)为例说明, 如果要配制 100 mL 2.5 mg/mL 的工作液, 您可以先取0.5g CMC Na并将其溶解于100mL ddH2O中，得到0.5%CMC-Na澄清溶液；然后将250 mg待测化合物加到100 mL前述 0.5%CMC Na溶液中，得到悬浮液。

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口服配方 3: 溶解于 PEG400 (聚乙二醇400)
口服配方 4: 悬浮于0.2% Carboxymethyl cellulose (羧甲基纤维素)
口服配方 5: 溶解于0.25% Tween 80 and 0.5% Carboxymethyl cellulose (羧甲基纤维素)
口服配方 6: 做成粉末与食物混合

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注意: 以上为较为常见方法，仅供参考， InvivoChem并未独立验证这些配方的准确性。具体溶剂的选择首先应参照文献已报道溶解方法、配方或剂型，对于某些尚未有文献报道溶解方法的化合物，需通过前期实验来确定（建议先取少量样品进行尝试），包括产品的溶解情况、梯度设置、动物的耐受性等。

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
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6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们;
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