Identification

Name
Trovafloxacin
Accession Number
DB00685  (APRD01281)
Type
Small Molecule
Groups
Approved, Investigational, Withdrawn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 It was withdrawn from the market due to the risk of hepatotoxicity.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
Synonyms
  • trovafloxacino
External IDs
CP-99219
Product Ingredients
IngredientUNIICASInChI Key
Trovafloxacin hydrochloride546454T03O146961-34-4VOYNIHWZMLJQHF-AHZSKCOESA-N
Trovafloxacin mesylate0P1LKO80WN147059-75-4DYNZICQDCVYXFW-AHZSKCOESA-N
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Trovan Tablets 100mgTablet100 mgOralPfizer1998-12-232001-11-22Canada
Trovan Tablets 200mgTablet200 mgOralPfizer1998-12-232001-11-22Canada
International/Other Brands
Trovan (Pfizer)
Categories
UNII
9F388J00UK
CAS number
147059-72-1
Weight
Average: 416.36
Monoisotopic: 416.109624848
Chemical Formula
C20H15F3N4O3
InChI Key
WVPSKSLAZQPAKQ-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])[C@H]2N)C1=NC2=C(C=C1F)C(=O)C(=CN2C1=C(F)C=C(F)C=C1)C(O)=O

Pharmacology

Indication

For 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.

Pharmacodynamics

Trovafloxacin 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 action

Trovafloxacin 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.

TargetActionsOrganism
ADNA gyrase subunit A
inhibitor
Haemophilus influenzae (strain ATCC 51907 / DSM 11121 / KW20 / Rd)
ADNA topoisomerase 4 subunit A
inhibitor
Haemophilus influenzae (strain ATCC 51907 / DSM 11121 / KW20 / Rd)
UDNA topoisomerase 2-alpha
inhibitor
Human
Absorption

Well-absorbed from the gastrointestinal tract after oral administration and does not depend on concomitant food intake. The absolute bioavailability is approximately 88%.

Volume of distribution
Not Available
Protein binding

The 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).

Route of elimination

Approximately 50% of an oral dose is excreted unchanged (43% in the feces and 6% in the urine).

Half life

Following 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.

Clearance
Not Available
Toxicity

Symptoms of overdose include convulsions, decreased activity, diarrhea, sleepiness, tremors, and/or vomiting.

Affected organisms
  • Enteric bacteria and other eubacteria
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
(R)-warfarinThe therapeutic efficacy of (R)-warfarin can be increased when used in combination with Trovafloxacin.
(S)-WarfarinThe therapeutic efficacy of (S)-Warfarin can be increased when used in combination with Trovafloxacin.
2,4-thiazolidinedioneThe therapeutic efficacy of 2,4-thiazolidinedione can be increased when used in combination with Trovafloxacin.
3-isobutyl-1-methyl-7H-xanthineThe metabolism of 3-isobutyl-1-methyl-7H-xanthine can be decreased when combined with Trovafloxacin.
4-hydroxycoumarinThe therapeutic efficacy of 4-hydroxycoumarin can be increased when used in combination with Trovafloxacin.
6-O-benzylguanineThe metabolism of 6-O-benzylguanine can be decreased when combined with Trovafloxacin.
7-DeazaguanineThe metabolism of 7-Deazaguanine can be decreased when combined with Trovafloxacin.
7,9-DimethylguanineThe metabolism of 7,9-Dimethylguanine can be decreased when combined with Trovafloxacin.
8-azaguanineThe metabolism of 8-azaguanine can be decreased when combined with Trovafloxacin.
8-chlorotheophyllineThe metabolism of 8-chlorotheophylline can be decreased when combined with Trovafloxacin.
Food Interactions
Not Available

References

General References
Not Available
External Links
KEGG Compound
C07664
PubChem Compound
62959
PubChem Substance
46508751
ChemSpider
16736478
BindingDB
50146361
ChEBI
9763
ChEMBL
CHEMBL428
Therapeutic Targets Database
DAP000652
PharmGKB
PA164749184
HET
TR6
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Trovafloxacin
ATC Codes
J01MA13 — Trovafloxacin
PDB Entries
4koe / 4z2e / 4z53

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4CompletedNot AvailableBacteremia / Endocarditis / Sepsis / Staphylococcus Aureus1

Pharmacoeconomics

Manufacturers
  • Pfizer chemicals div pfizer inc
  • Pfizer central research
Packagers
  • Pfizer Inc.
Dosage forms
FormRouteStrength
TabletOral100 mg
TabletOral200 mg
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US5164402No1992-11-172009-11-17Us
CA2023217No1996-12-102010-08-14Canada
US6187341No1999-01-202019-01-20Us

Properties

State
Solid
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 RuleNoChemAxon
MDDR-like RuleNoChemAxon
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)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
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 / Aminopiperidines / Aminopyridines and derivatives / Fluorobenzenes / Aryl fluorides / Imidolactams / Vinylogous amides / Pyrrolidines
show 11 more
Substituents
Naphthyridine carboxylic acid / Fluoroquinolone / Pyridine carboxylic acid / Pyridine carboxylic acid or derivatives / Dialkylarylamine / 4-aminopiperidine / Aminopyridine / Halobenzene / Fluorobenzene / Aryl fluoride
show 28 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
tertiary amino compound, azabicycloalkane, monocarboxylic acid, primary amino compound, amino acid, difluorobenzene, 1,8-naphthyridine derivative, quinolone antibiotic, fluoroquinolone antibiotic (CHEBI:9763)

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, 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. 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
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. 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 segr...
Gene Name
TOP2A
Uniprot ID
P11388
Uniprot Name
DNA topoisomerase 2-alpha
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]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Inhibitor
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. Raaska K, Neuvonen PJ: Ciprofloxacin increases serum clozapine and N-desmethylclozapine: a study in patients with schizophrenia. Eur J Clin Pharmacol. 2000 Nov;56(8):585-9. [PubMed:11151749]

Drug created on June 13, 2005 07:24 / Updated on November 02, 2018 09:08