Identification

Name
Gemifloxacin
Accession Number
DB01155  (APRD00053)
Type
Small Molecule
Groups
Approved, Investigational
Description

Gemifloxacin is an oral broad-spectrum quinolone antibacterial agent used in the treatment of acute bacterial exacerbation of chronic bronchitis and mild-to-moderate pneumonia. Gemifloxacin acts by inhibiting DNA synthesis through the inhibition of both DNA gyrase and topoisomerase IV, which are essential for bacterial growth.

Structure
Thumb
Synonyms
  • Factiv
  • Gemifloxacin mesilate
  • gemifloxacin mesylate
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
FactiveTablet320 mg/1OralChiesi Pharmaceuticals Inc.2003-04-042015-03-31Us
FactiveTablet320 mgOralOscient Pharmaceuticals Corporation2006-11-242009-02-19Canada
FactiveTablet320 mg/1OralVansen Pharma Inc.2003-04-04Not applicableUs
FactiveTablet320 mg/1OralMerus Labs International Inc.2003-04-04Not applicableUs
FactiveTablet, film coated320 mg/1OralOscient Pharmaceuticals Corporation2006-06-13Not applicableUs
Categories
UNII
OKR68Y0E4T
CAS number
175463-14-6
Weight
Average: 389.3809
Monoisotopic: 389.149932358
Chemical Formula
C18H20FN5O4
InChI Key
ZRCVYEYHRGVLOC-HYARGMPZSA-N
InChI
InChI=1S/C18H20FN5O4/c1-28-22-14-8-23(6-9(14)5-20)17-13(19)4-11-15(25)12(18(26)27)7-24(10-2-3-10)16(11)21-17/h4,7,9-10H,2-3,5-6,8,20H2,1H3,(H,26,27)/b22-14+
IUPAC Name
7-[(4Z)-3-(aminomethyl)-4-(methoxyimino)pyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid
SMILES
CO\N=C1/CN(CC1CN)C1=NC2=C(C=C1F)C(=O)C(=CN2C1CC1)C(O)=O

Pharmacology

Indication

For the treatment of bacterial infection caused by susceptible strains such as S. pneumoniae, H. influenzae, H. parainfluenzae, or M. catarrhalis, S. pneumoniae (including multi-drug resistant strains [MDRSP]), M. pneumoniae, C. pneumoniae, or K. pneumoniae.

Associated Conditions
Pharmacodynamics

Gemifloxacin is a quinolone/fluoroquinolone antibiotic. Gemifloxacin 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. Gemifloxacin is a broad-spectrum antibiotic that is active against both Gram-positive and Gram-negative bacteria.

Mechanism of action

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

TargetActionsOrganism
ADNA topoisomerase 4 subunit A
inhibitor
Haemophilus influenzae (strain ATCC 51907 / DSM 11121 / KW20 / Rd)
ADNA gyrase subunit A
inhibitor
Haemophilus influenzae (strain ATCC 51907 / DSM 11121 / KW20 / Rd)
Absorption

Rapidly absorbed from the gastrointestinal tract. The absolute bioavailability averages approximately 71%.

Volume of distribution
  • 1.66 to 12.12 L/kg
Protein binding

60-70%

Metabolism

Gemifloxacin is metabolized to a limited extent by the liver. All metabolites formed are minor (<10% of the administered oral dose); the principal ones are N-acetyl gemifloxacin, the E-isomer of gemifloxacin and the carbamyl glucuronide of gemifloxacin.

Route of elimination

Gemifloxacin and its metabolites are excreted via dual routes of excretion.Following oral administration of gemifloxacin to healthy subjects, a mean (± SD) of 61 ± 9.5% of the dose was excreted in the feces and 36 ± 9.3% in the urine as unchanged drug and metabolites. The mean (± SD) renal clearance following repeat doses of 320 mg was approximately 11.6 ± 3.9 L/hr (range 4.6-6 L/hr), which indicates active secretion is involved in the renal excretion of gemifloxacin.

Half life

7 (± 2) hours

Clearance
  • renal cl=11.6+/- 3.9 L/hr [Healthy subjects receiving repeat doses of 320 mg orally]
Toxicity
Not Available
Affected organisms
  • Enteric bacteria and other eubacteria
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
(4R)-limonene(4R)-limonene may increase the neuroexcitatory activities of Gemifloxacin.
16-BromoepiandrosteroneThe risk or severity of adverse effects can be increased when 16-Bromoepiandrosterone is combined with Gemifloxacin.
19-norandrostenedioneThe risk or severity of adverse effects can be increased when 19-norandrostenedione is combined with Gemifloxacin.
5-androstenedioneThe risk or severity of adverse effects can be increased when 5-androstenedione is combined with Gemifloxacin.
AcarboseThe therapeutic efficacy of Acarbose can be increased when used in combination with Gemifloxacin.
AceclofenacAceclofenac may increase the neuroexcitatory activities of Gemifloxacin.
AcemetacinAcemetacin may increase the neuroexcitatory activities of Gemifloxacin.
AcenocoumarolThe therapeutic efficacy of Acenocoumarol can be increased when used in combination with Gemifloxacin.
AcetyldigitoxinAcetyldigitoxin may decrease the cardiotoxic activities of Gemifloxacin.
AcetyldigoxinAcetyldigoxin may decrease the cardiotoxic activities of Gemifloxacin.
Food Interactions
  • Take without regard to meals.

References

Synthesis Reference
US5633262
General References
Not Available
External Links
Human Metabolome Database
HMDB0015286
KEGG Drug
D02471
PubChem Compound
9571107
PubChem Substance
46507905
ChemSpider
7845573
BindingDB
50178917
ChEBI
101853
ChEMBL
CHEMBL430
Therapeutic Targets Database
DAP000851
PharmGKB
PA10088
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
PDRhealth
PDRhealth Drug Page
Wikipedia
Gemifloxacin
ATC Codes
J01MA15 — Gemifloxacin
FDA label
Download (139 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
0Not Yet RecruitingTreatmentRhinoscleroma1
3Unknown StatusTreatmentBacterial Infection Due to Helicobacter Pylori (H. Pylori)1
4CompletedTreatmentGonorrhoea1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
  • Cornerstone Pharmacy
  • Oscient Pharmaceuticals
  • Patheon Inc.
Dosage forms
FormRouteStrength
TabletOral320 mg
TabletOral320 mg/1
Tablet, film coatedOral320 mg/1
Prices
Unit descriptionCostUnit
Factive 5 320 mg tablet Box148.08USD box
Factive 320 mg tablet28.48USD tablet
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US5633262No1995-06-152015-06-15Us
US6262071No1999-09-212019-09-21Us
US6331550No1999-09-212019-09-21Us
US6340689No1999-09-142019-09-14Us
US6455540No1999-09-212019-09-21Us
US6803376No1999-09-212019-09-21Us
US5776944No1997-04-042017-04-04Us
US6723734No1998-03-202018-03-20Us

Properties

State
Solid
Experimental Properties
PropertyValueSource
water solubilityFreely soluble at neutral pH (350 mg/mL at 37 °C, pH 7.0).Not Available
logP2.3Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.21 mg/mLALOGPS
logP-0.82ALOGPS
logP-0.92ChemAxon
logS-3.3ALOGPS
pKa (Strongest Acidic)5.53ChemAxon
pKa (Strongest Basic)9.53ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count9ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area121.35 Å2ChemAxon
Rotatable Bond Count5ChemAxon
Refractivity99.74 m3·mol-1ChemAxon
Polarizability39.3 Å3ChemAxon
Number of Rings4ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.9866
Blood Brain Barrier-0.5099
Caco-2 permeable-0.5644
P-glycoprotein substrateSubstrate0.8404
P-glycoprotein inhibitor INon-inhibitor0.85
P-glycoprotein inhibitor IIInhibitor0.6012
Renal organic cation transporterNon-inhibitor0.5751
CYP450 2C9 substrateNon-substrate0.8462
CYP450 2D6 substrateNon-substrate0.7919
CYP450 3A4 substrateNon-substrate0.5148
CYP450 1A2 substrateNon-inhibitor0.745
CYP450 2C9 inhibitorNon-inhibitor0.6642
CYP450 2D6 inhibitorNon-inhibitor0.809
CYP450 2C19 inhibitorNon-inhibitor0.6581
CYP450 3A4 inhibitorInhibitor0.5418
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.7405
Ames testAMES toxic0.6124
CarcinogenicityNon-carcinogens0.7902
BiodegradationNot ready biodegradable1.0
Rat acute toxicity2.5170 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.8366
hERG inhibition (predictor II)Non-inhibitor0.6715
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Taxonomy

Description
This compound belongs to the class of organic compounds known as naphthyridine carboxylic acids and derivatives. These are compounds containing a naphthyridine moiety, where one of the ring atoms bears a carboxylic acid group.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Diazanaphthalenes
Sub Class
Naphthyridines
Direct Parent
Naphthyridine carboxylic acids and derivatives
Alternative Parents
Fluoroquinolones / Pyridinecarboxylic acids / Dialkylarylamines / Aminopyridines and derivatives / Aryl fluorides / Imidolactams / Vinylogous amides / Pyrrolidines / Heteroaromatic compounds / Oxime ethers
show 10 more
Substituents
Naphthyridine carboxylic acid / Fluoroquinolone / Pyridine carboxylic acid / Pyridine carboxylic acid or derivatives / Dialkylarylamine / Aminopyridine / Imidolactam / Pyridine / Aryl fluoride / Aryl halide
show 23 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
monocarboxylic acid, 1,8-naphthyridine derivative, quinolone antibiotic, fluoroquinolone antibiotic (CHEBI:101853)

Targets

Kind
Protein
Organism
Haemophilus influenzae (strain ATCC 51907 / DSM 11121 / KW20 / Rd)
Pharmacological action
Yes
Actions
Inhibitor
General Function
Dna topoisomerase type ii (atp-hydrolyzing) activity
Specific Function
Topoisomerase IV is essential for chromosome segregation. It relaxes supercoiled DNA. Performs the decatenation events required during the replication of a circular DNA molecule.
Gene Name
parC
Uniprot ID
P43702
Uniprot Name
DNA topoisomerase 4 subunit A
Molecular Weight
83366.24 Da
References
  1. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. [PubMed:17139284]
  2. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. [PubMed:17016423]
  3. Alkorta M, Gimenez MJ, Vicente D, Aguilar L, Perez-Trallero E: In vivo activity of gemifloxacin, moxifloxacin and levofloxacin against pneumococci with gyrA and parC point mutations in a sepsis mouse model measured with the all or nothing mortality end-point. Int J Antimicrob Agents. 2005 Feb;25(2):163-7. [PubMed:15664487]
  4. Yague G, Morris JE, Pan XS, Gould KA, Fisher LM: Cleavable-complex formation by wild-type and quinolone-resistant Streptococcus pneumoniae type II topoisomerases mediated by gemifloxacin and other fluoroquinolones. Antimicrob Agents Chemother. 2002 Feb;46(2):413-9. [PubMed:11796351]
  5. LaPlante KL, Rybak MJ, Tsuji B, Lodise TP, Kaatz GW: Fluoroquinolone resistance in Streptococcus pneumoniae: area under the concentration-time curve/MIC ratio and resistance development with gatifloxacin, gemifloxacin, levofloxacin, and moxifloxacin. Antimicrob Agents Chemother. 2007 Apr;51(4):1315-20. Epub 2007 Feb 12. [PubMed:17296740]
Kind
Protein
Organism
Haemophilus influenzae (strain ATCC 51907 / DSM 11121 / KW20 / Rd)
Pharmacological action
Yes
Actions
Inhibitor
General Function
Dna topoisomerase type ii (atp-hydrolyzing) activity
Specific Function
DNA gyrase negatively supercoils closed circular double-stranded DNA in an ATP-dependent manner and also catalyzes the interconversion of other topological isomers of double-stranded DNA rings, inc...
Gene Name
gyrA
Uniprot ID
P43700
Uniprot Name
DNA gyrase subunit A
Molecular Weight
97817.145 Da
References
  1. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. [PubMed:17139284]
  2. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. [PubMed:17016423]
  3. Ruiz J, Marco F, Sierra JM, Aguilar L, Garcia-Mendez E, Mensa J, Jimenez De Anta MT, Vila J: In vitro activity of gemifloxacin against clinical isolates of Neisseria gonorrhoeae with and without mutations in the gyrA gene. Int J Antimicrob Agents. 2003 Jul;22(1):73-6. [PubMed:12842332]
  4. Alkorta M, Gimenez MJ, Vicente D, Aguilar L, Perez-Trallero E: In vivo activity of gemifloxacin, moxifloxacin and levofloxacin against pneumococci with gyrA and parC point mutations in a sepsis mouse model measured with the all or nothing mortality end-point. Int J Antimicrob Agents. 2005 Feb;25(2):163-7. [PubMed:15664487]
  5. Yague G, Morris JE, Pan XS, Gould KA, Fisher LM: Cleavable-complex formation by wild-type and quinolone-resistant Streptococcus pneumoniae type II topoisomerases mediated by gemifloxacin and other fluoroquinolones. Antimicrob Agents Chemother. 2002 Feb;46(2):413-9. [PubMed:11796351]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Inhibitor
Curator comments
This drug is a quinolone derivative, and these agents are known to inhibit CYP1A2.
General Function
Oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, reduced flavin or flavoprotein as one donor, and incorporation of one atom of oxygen
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP1A2
Uniprot ID
P05177
Uniprot Name
Cytochrome P450 1A2
Molecular Weight
58293.76 Da
References
  1. Shahzadi A, Javed I, Aslam B, Muhammad F, Asi MR, Ashraf MY, Zia-ur-Rahman: Therapeutic effects of ciprofloxacin on the pharmacokinetics of carbamazepine in healthy adult male volunteers. Pak J Pharm Sci. 2011 Jan;24(1):63-8. [PubMed:21190921]
  2. Fuhr U, Strobl G, Manaut F, Anders EM, Sorgel F, Lopez-de-Brinas E, Chu DT, Pernet AG, Mahr G, Sanz F, et al.: Quinolone antibacterial agents: relationship between structure and in vitro inhibition of the human cytochrome P450 isoform CYP1A2. Mol Pharmacol. 1993 Feb;43(2):191-9. [PubMed:8429824]
  3. Get to Know an Enzyme: CYP1A2 [Link]

Drug created on June 13, 2005 07:24 / Updated on October 01, 2018 15:37