Levofloxacin

HCID 149096CAS 100986-85-4

基本情報

標準SMILES
C[C@H]1COc2c(N3CCN(C)CC3)c(F)cc3c(=O)c(C(=O)O)cn1c23
InChIKey
GSDSWSVVBLHKDQ-JTQLQIEISA-N
分子式
C18H20FN3O4
平均分子量
361.4 g/mol
単同位体質量
361.14378434

概要

Levofloxacin is an optically active form of ofloxacin having (S)-configuration; an inhibitor of bacterial topoisomerase IV and DNA gyrase. It has a role as an antibacterial drug, an EC 5.99.1.3 [DNA topoisomerase (ATP-hydrolysing)] inhibitor, a topoisomerase IV inhibitor and a DNA synthesis inhibitor. It is a 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, a quinolone antibiotic and a fluoroquinolone antibiotic. It is a conjugate acid of a levofloxacin(1-). It is an enantiomer of a dextrofloxacin.

名称と識別子

優先名称
Levofloxacin
IUPAC
(2S)-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

名称と別名

LEVOFLOXACIN100986-85-4LevaquinQuixin(-)-OfloxacinIquixCravit(S)-OfloxacinLevofloxacineTavanicLevofloxacinoLevofloxacinum
名称をさらに表示
ElequineOftaquixL-OfloxacinFloxacinLevofloxacin AnhydrousDR-3355NofaxinVolequin

データベース識別子

CAS
100986-85-4
PubChem CID
149096
DTXSID
DTXSID0041060
ChEMBL
CHEMBL33、CHEMBL5315124
ChEBI
CHEBI:63598
UNII
RIX4E89Y14
EC Number
600-146-0
Nikkaji
J142.436J

物性

構造計算による物性

XLogP
-0.4
極性表面積
73.3 Ų
水素結合供与体数
1
水素結合受容体数
8
回転可能結合数
2
重原子数
26

実験および物理化学的性質

Drugs · 4 件

Pharmaceuticals -> Anti infectives for systemic use -> Antibacterials for systemic use

Pharmaceuticals -> Antibiotics

Pharmaceuticals -> Used in Switzerland

Pharmaceuticals -> Antibiotics

LogPlog Kow = -0.39
Color/Form · 2 件

Light yellowish -white to yellow-white crystal or crystalline powder

Needles from ethanol + ethyl ether

Solubility · 3 件

Sparingly soluble

Freely soluble in glacial acetic acid, chloroform; sparingly soluble in water

>54.2 [ug/mL] (The mean of the results at pH 7.4)

Human Drugs · 6 件

Breast Feeding; Lactation; Milk, Human; Anti-Infective Agents; Antibacterial Agents; Quinolones; Fluoroquinolones

FDA approved drugs -> Active ingredient

EMA approved medicines: Human medicine

FDA approved drugs -> Active ingredient

Pharmaceuticals

Antituberculosis medicines

DecompositionWhen heated to decomposition material emits toxic fumes of /nitrogen oxides and hydrogen fluoride/.

安全と法規制

GHS分類

GHS Classification · 4 件

Danger

H302 (98.3%): Harmful if swallowed [Warning Acute toxicity, oral]

P203, P233, P260, P261, P263, P264, P270, P271, P272, P280, P284, P301+P317, P302+P352, P304+P340, P318, P321, P330, P333+P317, P342+P316, P362+P364, P403, P405, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 174 reports by companies from 11 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

危険有害性情報

Fire PotentialThis material is assumed to be combustible.
FDA Requirements · 1 件

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including levofloxacin, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

Toxic Combustion ProductsEmits toxic fumes under fire conditions.
Hazard Classes and CategoriesAcute Tox. 4 (98.3%)

安全と保護具

Fire Fighting ProceduresWater spray, dry chemical, carbon dioxide, or foam as appropriate for surrounding fire and materials.
Storage ConditionsStore in tight, light-resistant container as defined in the USP-NF. This material should be handled and stored per label instructions to ensure product integrity.
Cleanup Methods · 1 件

Wear approved respiratory protection, chemically compatible gloves and protective clothing. Wipe up spillage or collect spillage using a high efficiency vacuum cleaner. Avoid breathing dust. Place spillage in appropriately labelled container for disposal. Wash spill site.

Disposal Methods · 2 件

SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.

SRP: At the time of review, regulatory criteria for small quantity disposal are subject to significant revision, however, household quantities of waste pharmaceuticals may be managed as follows: Mix with wet cat litter or coffee grounds, double bag in plastic, discard in trash.

Preventive Measures · 4 件

Engineering controls such as exhaust ventilation are recommended.

As with all dry powders it is advisable to ground mechanical equipment in contact with dry material to dissipate the potential buildup of static electricity.

As a general rule, when handling USP Reference Standards avoid all contact and inhalation of dust, mists, and/or vapors associated with the material. Wash thoroughly after handling.

SRP: Local exhaust ventilation should be applied wherever there is an incidence of point source emissions or dispersion of regulated contaminants in the work area. Ventilation control of the contaminant as close to its point of generation is both the most economical and safest method to minimize personnel exposure to airborne contaminants. Ensure that the local ventilation moves the contaminant away from the worker.

Personal Protective Equipment (PPE) · 1 件

Respiratory Protection: Use a NIOSH-approved respirator, if it is determined to be necessary by an industrial hygiene survey involving air monitoring. In the event that a respirator is not required, an approved dust mask should be used. Gloves: Chemically compatible. Eye Protection: Safety glasses or goggles. Protective Clothing: Protect exposed skin.

毒性情報

TreatmentIn the event of an acute overdosage, the stomach should be emptied. The patient should be observed and appropriate hydration maintained. Levofloxacin is not efficiently removed by hemodialysis or peritoneal dialysis. (L1009)
Interactions · 5 件

Warfarin: Potential pharmacologic interaction (increased prothrombin time). Monitor prothrombin time or other suitable coagulation tests and monitor for bleeding.

Theophylline: Pharmacokinetic interaction unlikely. However, pharmacokinetic interaction (increased theophylline half-life and increased risk of theophylline-related adverse effects) occurs with some other quinolones. Closely monitor serum theophylline concentrations and adjust theophylline dosage accordingly; consider that adverse theophylline effects (e.g., seizures) may occur with or without elevated theophylline concentrations.

Sucralfate: Potential pharmacokinetic interaction (decreased levofloxacin absorption); no pharmacokinetic interaction if given 2 hours apart. Administer levofloxacin at least 2 hours before or 2 hours after sucralfate.

Probenecid: Potential pharmacokinetic interaction (increased levofloxacin AUC and half-life). Not considered clinically important; dosage adjustments are not required.

For more Interactions (Complete) data for Levofloxacin (16 total), please visit the HSDB record page.

Health Effects · 1 件

Irreversible peripheral neuropathy, central nervous system toxicity, cardiovascular toxicity, tendon / articular toxicity, and hepatic toxicity. Toxic epidermal necrolysis, coagulation abnormalities and pancytopenia are other possible adverse effect of levofloxacin. Administration of commercial levofloxin (Levaquin), increased risk of tendinitis and tendon rupture in all ages. This adverse reaction most frequently involves the Achilles tendon (L1009, L1017).

Hepatotoxicity · 1 件

In short term studies, levofloxacin has been associated with minor elevations in serum ALT and AST levels in 2% to 5% of patients. The abnormalities were usually asymptomatic and transient and rarely require dose modification. With its wide scale use, levofloxacin has been implicated in in at least 50 instances of clinically apparent liver injury mostly in isolated case reports. The clinical presentation and course are typical of the hepatotoxicity of other fluoroquinolones, and the injury is likely a class effect. The latency to onset is usually short (1 to 3 weeks) and the onset is often abrupt with a hepatocellular or mixed pattern of injury, jaundice and, in some instances, hepatic failure. Cholestatic hepatitis can also occur. Immunoallergic features such as fever, rash and eosinophilia are common, but not particularly prominent. Autoantibodies are rare. The liver injury is usually self-limited, but several cases of acute liver failure have been linked to fluoroquinolones as well as instances of prolonged jaundice, cholestasis and vanishing bile duct syndrome. Levofloxacin, like ciprofloxacin, has also been implicated hypersensitivity reactions including rare cases of Stevens Johnson syndrome and toxic epidermal necrolysis, which may be accompanied by liver injury. While liver injury from levofloxacin is rare, the fluoroquinolones collectively are among the most frequent causes of clinically apparent liver injury including fatal cases and cases of chronic liver injury and bile duct paucity.

Ecotoxicity Values · 3 件

EC50; Species: Microcystis aeruginosa (Blue-Green Algae); Conditions: freshwater, static, 20 °C; Concentration: 7.9 ug/L for 5 days (95% confidence interval: 6.4-9.4 ug/L); Effect: population, decreased chlorophyll A concentration /100% purity formulation/

EC50; Species: Pseudokirchneriella subcapitata (Green Algae); Conditions: freshwater, static, 20 °C; Concentration: 7400 ug/L for 3 days (95% confidence interval: 6400-8400 ug/L); Effect: population, decreased chlorophyll A concentration /100% purity formulation/

EC50; Species: Lemna minor (Duckweed); Conditions: freshwater, renewal, 20 °C; Concentration: 51 ug/L for 7 days (95% confidence interval: 8.6-94 ug/L); Effect: population, decreased abundance (counted number of fronds) /100% purity formulation/

Environmental Fate · 4 件

TERRESTRIAL FATE: Based on a classification scheme(1), a Koc value of 44,143 for the sterioisomer,ofloxacin(2) indicates that levofloxacin is expected to be immobile in soil(SRC). The pKa1 of levofloxacin is 6.24 (carboxylic acid moiety)(1) and pKa2 = 8.74 for analogous ciprofloxacin for the nitrogen on the piperazinyl ring(3); at pHs greater than 6.24, the acid will be primarily dissociated and at pHs less than approximately 8.74, the nitrogen will be primarily protonated(SRC); therefore, levofloxacin will have an ionic charge at any environmental pH(SRC). Volatilization from moist soil is not expected because the compound exists as an ion and ions do not volatilize. Levofloxacin is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 9.8X10-13 mm Hg at 25 °C(SRC), determined from a fragment constant method(4). Using the OECD closed bottle biodegradation study, 0% degradation over a 40-day incubation period was observed for analogous ciprofloxacin(5), indicating that biodegradation may not be an important environmental fate process for levofloxacin in soil(SRC).

AQUATIC FATE: Based on a classification scheme(1), a Koc value of 44,143(2) indicates that levofloxacin is expected to adsorb to suspended solids and sediment(SRC). The pKa1 of levofloxacin is 6.24 (carboxylic acid moiety)(1) and pKa2 = 8.74 for analogous ciprofloxacin for the nitrogen on the piperazinyl ring(3); at pHs greater than 6.24, the acid will be primarily dissociated and at pHs less than approximately 8.74, the nitrogen will be primarily protonated(SRC); therefore, levofloxacin will have an ionic charge at any environmental pH(SRC). Due to this ionic state, volatilization from water surfaces is not expected to be an important fate process(SRC). According to a classification scheme(4), an estimated BCF of 3(SRC), from a log Kow of -0.39 for sterioisomer ofloxacin(5) and a regression-derived equation(6), suggests the potential for bioconcentration in aquatic organisms is low(SRC). Using the OECD closed bottle biodegradation study, 0% degradation over a 40-day incubation period was observed for analogous ciprofloxacin(7), indicating that biodegradation may not be an important environmental fate process for levofloxacin in water(SRC).

AQUATIC FATE: Using outdoor aquatic field microcosms, levofloxacin, at concentrations of 1.00, 10.00, 100.00, and 300.00 ug/L exhibited half-lives of 6.2, 6.5, 6.0, and 6.3 days, overall mean of 6.3 days, with photodegradation being the main loss process. Photoproducts have been identified as analogues altered at the N-methylpiperazine moiety and reached a maximum by 2 hours after which their concentrations decreased(1). Therefore levofloxacin may be susceptible to direct photolysis by sunlight(SRC).

ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), levofloxacin, which has an estimated vapor pressure of 8.8X10-13 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), is expected to exist solely in the particulate phase in the ambient atmosphere. Particulate-phase levofloxacin may be removed from the air by wet or dry deposition(SRC). Levofloxacin in solution is susceptible to photodegradation in natural light, exhibiting a mean half-life of 6.3 days(4), and therefore may be susceptible to direct photolysis by sunlight(SRC).

法規制情報

FDA Requirements · 1 件

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including levofloxacin, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

化学と産業

薬理情報

ATC Code · 6 件

J01MA12

J - Antiinfectives for systemic use

S - Sensory organs

QS - Sensory organs

QJ - Antiinfectives for systemic use

J01MA12

Protein BindingLevofloxacin is 24-38% protein-bound in plasma, primarily to albumin. The extent of protein-binding is independent of its plasma concentration.
Pharmacodynamics · 1 件

Levofloxacin is bactericidal and exerts its antimicrobial effects via inhibition of bacterial DNA replication. It has a relatively long duration of action in comparison with other antibiotics that allows for once or twice daily dosing. Levofloxacin is associated with QTc-interval prolongation and should be used with caution in patients with other risk factors for prolongation (e.g. hypokalemia, concomitant medications). Levofloxacin has demonstrated _in vitro_ activity against a number of aerobic gram-positive and gram-negative bacteria and may carry some activity against certain species of anaerobic bacteria and other pathogens such as _Chlamydia_ and _Legionella_. Resistance to levofloxacin may develop, and is generally due to mutations in DNA gyrase or topoisomerase IV, or via alterations to drug efflux. Cross-resistance may occur between levofloxacin and other fluoroquinolones, but is unlikely to develop between levofloxacin and other antibiotic classes (e.g. macrolides) due to significant differences in chemical structure and mechanism of action. As antimicrobial susceptibility patterns are geographically distinct, local antibiograms should be consulted to ensure adequate coverage of relevant pathogens prior to use.

Mechanism of Action · 3 件

Levofloxacin, like other fluoroquinolone antibiotics, exerts its antimicrobial activity via the inhibition of two key bacterial enzymes: DNA gyrase and topoisomerase IV. Both targets are type II topoisomerases, but have unique functions within the bacterial cell. DNA gyrase is an enzyme found only in bacteria that introduces negative supercoils into DNA during replication - this helps to relieve torsional strain caused by the introduction of positive supercoils during replication, and these negative supercoils are essential for chromosome condensation and the promotion of transcription initiation. It is comprised of four subunits (two A subunits and two B subunits) of which the A subunits appear to be the target of fluoroquinolone antibiotics. Bacterial topoisomerase IV, in addition to contributing to the relaxation of positive supercoils, is essential at the terminal stages of DNA replication and functions to “unlink” newly replicated chromosomes to allow for the completion of cell division. Inhibition of these enzymes by levofloxacin likely occurs via complexation with the topoisomerase enzymes. The end result is a blockade of DNA replication, thus inhibiting cell division and resulting in cell death.

Levofloxacin is the L-isomer of the racemate, ofloxacin, a quinolone antimicrobial agent. The antibacterial activity of ofloxacin resides primarily in the L-isomer. The mechanism of action of levofloxacin and other fluoroquinolone antimicrobials involves inhibition of bacterial topoisomerase IV and DNA gyrase (both of which are type II topoisomerases), enzymes required for DNA replication, transcription, repair and recombination.

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).

Biological Half-Life · 4 件

The average terminal elimination half-life of levofloxacin is 6-8 hours.

The mean terminal plasma elimination half-life of levofloxacin ranges from approximately 6 to 8 hours following single or multiple doses of levofloxacin given orally or intravenously.

The pharmacokinetics of oral levofloxacin and its penetration into inflammatory fluid were studied in 6 healthy male subjects (ages 18-45 yr) who received 500 mg drug every 12 hr for 5 doses or 500 mg every 24 hr for 3 doses in an open crossover design. ... Mean terminal elimination half-lives in plasma were 7.9 and 8 hr for the 2 regimens, respectively, and the same values were seen for inflammatory fluid. ...

After single oral administration of (14)C-levofloxacin at a dose of 20 mg kg(-1) under non-fasting conditions, the absorption, distribution and excretion of radioactivity were studied in albino and pigmented rats. ... The uveal tract concentrations reached the maximum value (C(max)) of 26.33 +/- 0.75 ug eq. g(-1) at 24 hr after dosing and declined slowly with a terminal half-life of 468.1 hr (19.5 days).

Metabolism/Metabolites · 3 件

Only 2 metabolites, desmethyl-levofloxacin and levofloxacin-N-oxide, have been identified in humans, neither of which appears to carry any relevant pharmacological activity. Following oral administration, less than 5% of the administered dose was recovered in the urine as these metabolites, indicating very little metabolism of levofloxacin in humans. The specific enzymes responsible for the demethylation and oxidation of levofloxacin have yet to be ascertained.

Levofloxacin is stereochemically stable in plasma and urine and does not invert metabolically to its enantiomer, D-ofloxacin. Levofloxacin undergoes limited metabolism in humans and is primarily excreted as unchanged drug in the urine. Following oral administration, approximately 87% of an administered dose was recovered as unchanged drug in urine within 48 hours, whereas less than 4% of the dose was recovered in feces in 72 hours. Less than 5% of an administered dose was recovered in the urine as the desmethyl and N-oxide metabolites, the only metabolites identified in humans. These metabolites have little relevant pharmacological activity.

Mainly excreted as unchanged drug (87%); undergoes limited metabolism in humans. Levofloxacin is rapidly and essentially completely absorbed after oral administration. It is distributed into body tissues, especially in the skin and lung tissues. Levofloxacin is stereochemically stable in plasma and urine and does not invert metabolically to its enantiomer, D-ofloxacin. Levofloxacin undergoes limited metabolism in humans and is primarily excreted as unchanged drug in the urine. Following oral administration, approximately 87% of an administered dose was recovered as unchanged drug in urine within 48 hours, whereas less than 4% of the dose was recovered in feces in 72 hours. Less than 5% of an administered dose was recovered in the urine as the desmethyl and N-oxide metabolites, the only metabolites identified in humans. These metabolites have little relevant pharmacological activity. Levofloxacin is excreted largely as unchanged drug in the urine (L1009). Route of Elimination: Mainly excreted as unchanged drug in the urine. Half Life: 6-8 hours

用途と製造

Uses · 3 件

MEDICATION

Use (kg; approx.) in Germany (2009): >7500

For the treatment of bacterial conjunctivitis caused by susceptible strains of the following organisms: <i>Corynebacterium</i> species, <i>Staphylococus aureus</i>, <i>Staphylococcus epidermidis</i>, <i>Streptococcus pneumoniae</i>, <i>Streptococcus</i> (Groups C/F/G), Viridans group streptococci, <i>Acinetobacter lwoffii</i>, <i>Haemophilus influenzae</i>, <i>Serratia marcescens</i>. Levofloxacin is a synthetic chemotherapeutic agent used to treat severe and life threatening bacterial infection (L1009).

Formulations/Preparations · 4 件

Table: Levofloxacin Preparations [Table#7973]

Parenteral Injection, for IV infusion: equivalent to levofloxacin 5 mg/mL (250, 500, or 750 mg) in 5% Dextrose; Levaquin in Dextrose Injection Premix (in flexible containers) (Ortho-McNeil).

Ophthalmic: Solution 0.5%, Quixin (Vistakon)

Tavanic (levofloxacin; 250 and 500 mg film-coated tablets and 5mg/mL solution for infusion)

Use ClassificationPharmaceuticals
General Manufacturing Information · 3 件

The more active levo isomer of ofloxacin (a racemic mixture of D,L,-isomers) that has improved activity against gram-potitive pathogens (in particular against S. pneumoniae) compared to ciprofloxacin.

Prepared as the hemihydrate

The methyl group at the C-3 position in the oxazine ring results in the formation of isoenantiomers; ofloxacin occurs as a racemic mixture of the two isomers. The S-(-)isomer is 8-128 times as active against susceptible gram-positive and gram-negative organisms as the R-(+)isomer and approximately twice as active as racemic ofloxacin.

関連反応

24 件

関連ノート

読み込み中…