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Identification
NameTrovafloxacin
Accession NumberDB00685  (APRD01281)
TypeSmall Molecule
GroupsApproved, Withdrawn
Description

Trovafloxacin (sold as Trovan by Pfizer) is a broad spectrum antibiotic that inhibits the uncoiling of supercoiled DNA in various bacteria by blocking the activity of DNA gyrase and topoisomerase IV. It was withdrawn from the market due to the risk of hepatotoxicity. It had better gram-positive bacterial coverage and less gram-negative coverage than the previous fluoroquinolones. [Wikipedia]

Structure
Thumb
SynonymsNot Available
External Identifiers
  • CP-99219
Approved Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Trovan I.V.liquid5 mgintravenousPfizer Canada Inc1998-12-232001-11-22Canada
Trovan Tablets 100mgtablet100 mgoralPfizer Canada Inc1998-12-232001-11-22Canada
Trovan Tablets 200mgtablet200 mgoralPfizer Canada Inc1998-12-232001-11-22Canada
Approved Generic Prescription ProductsNot Available
Approved Over the Counter ProductsNot Available
Unapproved/Other Products Not Available
International Brands
NameCompany
TrovanPfizer
Brand mixturesNot Available
Salts
Name/CASStructureProperties
Trovafloxacin mesylate
147059-75-4
Thumb
  • InChI Key: DYNZICQDCVYXFW-AHZSKCOESA-N
  • Monoisotopic Mass: 512.097740011
  • Average Mass: 512.46
DBSALT000992
Categories
UNII9F388J00UK
CAS number147059-72-1
WeightAverage: 416.36
Monoisotopic: 416.109624848
Chemical FormulaC20H15F3N4O3
InChI KeyWVPSKSLAZQPAKQ-CDMJZVDBSA-N
InChI
InChI=1S/C20H15F3N4O3/c21-8-1-2-15(13(22)3-8)27-7-12(20(29)30)17(28)9-4-14(23)19(25-18(9)27)26-5-10-11(6-26)16(10)24/h1-4,7,10-11,16H,5-6,24H2,(H,29,30)/t10-,11+,16+
IUPAC Name
7-[(1R,5S,6S)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl]-1-(2,4-difluorophenyl)-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid
SMILES
[H][C@@]12CN(C[C@]1([H])[[email protected]]2N)C1=NC2=C(C=C1F)C(=O)C(=CN2C1=C(F)C=C(F)C=C1)C(O)=O
Taxonomy
DescriptionThis 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.
KingdomOrganic compounds
Super ClassOrganoheterocyclic compounds
ClassDiazanaphthalenes
Sub ClassNaphthyridines
Direct ParentNaphthyridine carboxylic acids and derivatives
Alternative Parents
Substituents
  • Naphthyridine carboxylic acid
  • Fluoroquinolone
  • Pyridine carboxylic acid
  • Pyridine carboxylic acid or derivatives
  • Dialkylarylamine
  • 4-aminopiperidine
  • Aminopyridine
  • Halobenzene
  • Fluorobenzene
  • Aryl fluoride
  • Piperidine
  • Monocyclic benzene moiety
  • Aryl halide
  • Pyridine
  • Imidolactam
  • Benzenoid
  • Vinylogous amide
  • Pyrrolidine
  • Heteroaromatic compound
  • Amino acid
  • Amino acid or derivatives
  • Azacycle
  • Carboxylic acid derivative
  • Carboxylic acid
  • Organonitrogen compound
  • Organooxygen compound
  • Organic oxygen compound
  • Organic nitrogen compound
  • Primary amine
  • Amine
  • Hydrocarbon derivative
  • Organic oxide
  • Organofluoride
  • Primary aliphatic amine
  • Organohalogen compound
  • Aromatic heteropolycyclic compound
Molecular FrameworkAromatic heteropolycyclic compounds
External Descriptors
Pharmacology
IndicationFor treatment of infections caused by susceptible strains of the designated microorganisms in uncomplicated urethral gonorrhea in males and endocervical and rectal gonorrhea in females caused by Neisseria gonorrhoeae as well as non gonoccocal urethritis and cervicitis due to Chlamydia trachomatis.
PharmacodynamicsTrovafloxacin is a broad spectrum antibiotic that inhibits DNA supercoiling in various bacteria by blocking the activity of DNA gyrase and topoisomerase IV. It is not used widely due to the risk of hepatotoxicity. It tends to have better gram-positive bacterial coverage and less gram-negative coverage than the previous fluoroquinolones. Mechanism of action of fluoroquinolones including trovafloxacin is different from that of penicillins, cephalosporins, aminoglycosides, macrolides, and tetracyclines. Therefore fluoroquinolones may be active against pathogens that are resistant to these antibiotics. There is no cross-resistance between trovafloxacin and the mentioned classes of antibiotics. The overall results obtained from in vitro synergy studies, testing combinations of trovafloxacin with beta-lactams and aminoglycosides, indicate that synergy is strain specific and not commonly encountered. This agrees with results obtained previously with other fluoroquinolones. Resistance to trovafloxacin in vitro develops slowly via multiple-step mutation in a manner similar to other fluoroquinolones. Resistance to trovafloxacin in vitro occurs at a general frequency of between 1x10-7 to 10-10. Although cross-resistance has been observed between trovafloxacin and some other fluoroquinolones, some microorganisms resistant to other fluoroquinolones may be susceptible to trovafloxacin.
Mechanism of actionTrovafloxacin is a fluoronaphthyridone related to the fluoroquinolones with in vitro activity against a wide range of gram-negative and gram-positive aerobic and anaerobic microorganisms. The bactericidal action of trovafloxacin results from inhibition of DNA gyrase and topoisomerase IV. DNA gyrase is an essential enzyme that is involved in the replication, transcription, and repair of bacterial DNA. Topoisomerase IV is an enzyme known to play a key role in the partitioning of the chromosomal DNA during bacterial cell division.
Related Articles
AbsorptionWell-absorbed from the gastrointestinal tract after oral administration and does not depend on concomitant food intake. The absolute bioavailability is approximately 88%.
Volume of distributionNot Available
Protein bindingThe mean plasma protein bound fraction is approximately 76%, and is concentration-independent.
Metabolism

Metabolism Trovafloxacin is metabolized by conjugation (the role of cytochrome P450 oxidative metabolism of trovafloxacin is minimal). The major metabolites include the ester glucuronide, which appears in the urine (13% of the administered dose); and the N -acetyl metabolite, which appears in the feces and serum (9% and 2.5% of the administered dose, respectively). Other minor metabolites include diacid, hydroxycarboxylic acid, and sulfamate, which have been identified in both the feces and the urine in small amounts (< 4% of the administered dose).

SubstrateEnzymesProduct
Trovafloxacin
Not Available
SulfamateDetails
Route of eliminationApproximately 50% of an oral dose is excreted unchanged (43% in the feces and 6% in the urine).
Half lifeFollowing oral administration, half-life ranged from 9.1 hours to 12.2 hours over the dosage range of 100 to 200 mg tablets. Following intravenous infusion, half-life ranged from 9.4 to 12.7 hours over a dosage range of 100 to 300 mg.
ClearanceNot Available
ToxicitySymptoms of overdose include convulsions, decreased activity, diarrhea, sleepiness, tremors, and/or vomiting.
Affected organisms
  • Enteric bacteria and other eubacteria
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.9969
Blood Brain Barrier+0.8109
Caco-2 permeable+0.8867
P-glycoprotein substrateSubstrate0.5958
P-glycoprotein inhibitor INon-inhibitor0.9513
P-glycoprotein inhibitor IINon-inhibitor0.8319
Renal organic cation transporterNon-inhibitor0.7813
CYP450 2C9 substrateNon-substrate0.8731
CYP450 2D6 substrateNon-substrate0.8237
CYP450 3A4 substrateNon-substrate0.7022
CYP450 1A2 substrateNon-inhibitor0.7515
CYP450 2C9 inhibitorNon-inhibitor0.7908
CYP450 2D6 inhibitorNon-inhibitor0.834
CYP450 2C19 inhibitorNon-inhibitor0.6968
CYP450 3A4 inhibitorNon-inhibitor0.8746
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.7571
Ames testAMES toxic0.7022
CarcinogenicityNon-carcinogens0.888
BiodegradationNot ready biodegradable1.0
Rat acute toxicity2.3897 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9514
hERG inhibition (predictor II)Non-inhibitor0.7112
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397 )
Pharmacoeconomics
Manufacturers
  • Pfizer chemicals div pfizer inc
  • Pfizer central research
Packagers
Dosage forms
FormRouteStrength
Liquidintravenous5 mg
Tabletoral100 mg
Tabletoral200 mg
PricesNot Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US5164402 No1992-11-172009-11-17Us
CA2023217 No1996-12-102010-08-14Canada
US6187341 No1999-01-202019-01-20Us
Properties
StateSolid
Experimental Properties
PropertyValueSource
water solubility12.3 mg/L (at 25 °C)MCFARLAND,JW ET AL. (2001)
logP0.31DAYLIGHT (2002)
Predicted Properties
PropertyValueSource
Water Solubility0.0704 mg/mLALOGPS
logP0.86ALOGPS
logP0.14ChemAxon
logS-3.8ALOGPS
pKa (Strongest Acidic)5.41ChemAxon
pKa (Strongest Basic)9.44ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count7ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area99.76 Å2ChemAxon
Rotatable Bond Count3ChemAxon
Refractivity101.04 m3·mol-1ChemAxon
Polarizability38.12 Å3ChemAxon
Number of Rings5ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Mass Spec (NIST)Not Available
SpectraNot Available
References
Synthesis ReferenceNot Available
General ReferencesNot Available
External Links
ATC CodesJ01MA13
AHFS CodesNot Available
PDB EntriesNot Available
FDA labelNot Available
MSDSNot Available
Interactions
Drug InteractionsNot Available
Food InteractionsNot Available

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:
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, including catenanes and knotted rings.
Gene Name:
gyrA
Uniprot ID:
P43700
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. Brisse S, Milatovic D, Fluit AC, Verhoef J, Martin N, Scheuring S, Kohrer K, Schmitz FJ: Comparative in vitro activities of ciprofloxacin, clinafloxacin, gatifloxacin, levofloxacin, moxifloxacin, and trovafloxacin against Klebsiella pneumoniae, Klebsiella oxytoca, Enterobacter cloacae, and Enterobacter aerogenes clinical isolates with alterations in GyrA and ParC proteins. Antimicrob Agents Chemother. 1999 Aug;43(8):2051-5. [PubMed:10428935 ]
  4. Bebear CM, Grau O, Charron A, Renaudin H, Gruson D, Bebear C: Cloning and nucleotide sequence of the DNA gyrase (gyrA) gene from Mycoplasma hominis and characterization of quinolone-resistant mutants selected in vitro with trovafloxacin. Antimicrob Agents Chemother. 2000 Oct;44(10):2719-27. [PubMed:10991851 ]
  5. Gootz TD, Zaniewski RP, Haskell SL, Kaczmarek FS, Maurice AE: Activities of trovafloxacin compared with those of other fluoroquinolones against purified topoisomerases and gyrA and grlA mutants of Staphylococcus aureus. Antimicrob Agents Chemother. 1999 Aug;43(8):1845-55. [PubMed:10428901 ]
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
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. Rafii F, Park M, Novak JS: Alterations in DNA gyrase and topoisomerase IV in resistant mutants of Clostridium perfringens found after in vitro treatment with fluoroquinolones. Antimicrob Agents Chemother. 2005 Feb;49(2):488-92. [PubMed:15673722 ]
  4. Daporta MT, Munoz Bellido JL, Guirao GY, Hernandez MS, Garcia-Rodriguez JA: In vitro activity of older and newer fluoroquinolones against efflux-mediated high-level ciprofloxacin-resistant Streptococcus pneumoniae. Int J Antimicrob Agents. 2004 Aug;24(2):185-7. [PubMed:15288320 ]
  5. Ruiz J, Jurado A, Garcia-Mendez E, Marco F, Aguilar L, Jimenez de Anta MT, Vila J: Frequency of selection of fluoroquinolone-resistant mutants of Neisseria gonorrhoeae exposed to gemifloxacin and four other quinolones. J Antimicrob Chemother. 2001 Oct;48(4):545-8. [PubMed:11581235 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
inhibitor
General Function:
Ubiquitin binding
Specific Function:
Control of topological states of DNA by transient breakage and subsequent rejoining of DNA strands. Topoisomerase II makes double-strand breaks. Essential during mitosis and meiosis for proper segregation of daughter chromosomes. May play a role in regulating the period length of ARNTL/BMAL1 transcriptional oscillation (By similarity).
Gene Name:
TOP2A
Uniprot ID:
P11388
Molecular Weight:
174383.88 Da
References
  1. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352 ]
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Drug created on June 13, 2005 07:24 / Updated on July 23, 2016 01:52