DT-Web

DB00685 - Trovafloxacin


Identification
Name Trovafloxacin
Accession Number DB00685 (APRD01281)
Type small molecule
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 It was withdrawn from the market due to the risk of hepatotoxicity.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
MOL SDF PDB SMILES InChI
Categories (*)
Molecular Weight 416.3533
Groups approved
Monoisotopic Weight 416.109624981
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.
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.
Absorption Well-absorbed from the gastrointestinal tract after oral administration and does not depend on concomitant food intake. The absolute bioavailability is approximately 88%.
Protein binding The mean plasma protein bound fraction is approximately 76%, and is concentration-independent.
Biotransformation 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).
Toxicity Symptoms of overdose include convulsions, decreased activity, diarrhea, sleepiness, tremors, and/or vomiting.
Affected organisms
  • Enteric bacteria and other eubacteria
Interactions
Drug Interactions
Drug Mechanism of interaction
Aluminium Aluminum may decrease the absorption of orally administered Trovafloxacin. Administer Trovafloxacin 2 hours before or 6 hours after a dose of the aluminum containing agent to minimize the interaction.
Calcium Formation of non-absorbable complexes
Calcium Acetate Calcium may decrease the absorption of orally administered Trovafloxacin. Administer Trovafloxacin 2 hours before or 6 hours after a dose of the calcium containining agent to minimize the interaction.
Calcium Chloride Calcium may decrease the absorption of orally administered Trovafloxacin. Administer Trovafloxacin 2 hours before or 6 hours after a dose of the calcium containing agent to minimize the interaction.
Calcium Gluceptate Calcium may decrease the absorption of orally administered Trovafloxacin. Administer Trovafloxacin 2 hours before or 6 hours after a dose of the calcium containing agent to minimize the interaction.
Didanosine Didanosine may decrease the absorption of orally administered Trovafloxacin. The Didanosine formulation contains magnesium and aluminum ions that intefere with Trovafloxacin absorption. Administer Trovafloxacin 2 hours before or 6 hours after the Didanosine dose to minimize the interaction. This interaction is not observed with enteric coated Didanosine.
Iron Iron may decrease the absorption of orally administered Trovafloxacin. Administer Trovafloxacin 2 hours before or 6 hours after a dose of the iron containing agent to minimize the interaction.
Iron Dextran Formation of non-absorbable complexes
Magnesium Formation of non-absorbable complexes
Magnesium oxide Magnesium may decrease the absorption of orally administered Trovafloxacin. Administer Trovafloxacin 2 hours before or 6 hours after a dose of the magnesium containing agent to minimize the interaction.
Magnesium Sulfate Magnesium may decrease the absorption of orally administered Trovafloxacin. Administer Trovafloxacin 2 hours before or 6 hours after a dose of the magnesium containing agent to minimize the interaction.
Morphine Morphine may reduce serum levels of Trovafloxacin decreasing the efficacy of the antibiotic. IV doses of morphine should be administered at least 2 hours after a dose of Trovafloxacin given in a fasting state or 4 hours after if given in a fed state.
Quinapril Quinapril may decrease the absorption of orally administered Trovafloxacin. The Quinapril formulation contains magnesium ions that may intefere with Trovafloxacin absorption. Administer Trovafloxacin 2 hours before or 6 hours after the Quinapril dose to minimize the interaction.
Sevelamer Sevelamer may decrease the absorption of orally administered Trovafloxacin. The Sevelamer formulation contains iron that may intefere with Trovafloxacin absorption. Administer Trovafloxacin 2 hours before or 6 hours after the Sevelamer dose to minimize the interaction.
Sucralfate Sucralfate may decrease the absorption of orally administered Trovafloxacin. The Sucralfate formulation contains aluminum ions that may intefere with Trovafloxacin absorption. Administer Trovafloxacin 2 hours before or 6 hours after the Sucralfate dose to minimize the interaction.
Zinc Zinc may decrease the absorption of orally administered Trovafloxacin. Administer Trovafloxacin 2 hours before or 6 hours after a dose of the zinc containing agent to minimize the interaction.
Food Interactions Not Available

Targets


DNA gyrase subunit A
Name DNA gyrase subunit A
Gene Name gyrA
Pharmacological action yes
Actions inhibitor
References
  • Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. - Pubmed
  • 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
  • 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
  • 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
  • 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
DTHybrid score 0.9215
DNA topoisomerase 4 subunit A
Name DNA topoisomerase 4 subunit A
Gene Name parC
Pharmacological action yes
Actions inhibitor
References
  • Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. - Pubmed
  • 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
  • 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
  • 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
  • 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
DTHybrid score 0.8862
DNA topoisomerase 2-alpha
Name DNA topoisomerase 2-alpha
Gene Name TOP2A
Pharmacological action unknown
Actions inhibitor
References
  • Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. - Pubmed
DTHybrid score 0.7064

Predictions


Id Partner name Gene Name Score
6224 DNA gyrase subunit A gyrA 0.9215
886 DNA topoisomerase 4 subunit A parC 0.8862
6226 DNA topoisomerase 4 subunit A parC 0.8862
4200 Cytochrome P450 1A2 CYP1A2 0.1722
118 Organic cation/carnitine transporter 2 SLC22A5 0.0949
1735 Canalicular multispecific organic anion transporter 1 ABCC2 0.0802
1729 Solute carrier family 22 member 6 SLC22A6 0.0761
1588 Multidrug resistance protein 1 ABCB1 0.0703
862 Multidrug resistance-associated protein 1 ABCC1 0.0614
4512 Cytochrome P450 3A4 CYP3A4 0.0549
4192 DNA topoisomerase 2-beta TOP2B 0.044
833 Organic cation/carnitine transporter 1 SLC22A4 0.0392
4118 Cytochrome P450 3A5 CYP3A5 0.0346
4180 DNA-(apurinic or apyrimidinic site) lyase APEX1 0.0305
6144 Solute carrier family 22 member 2 SLC22A2 0.0305
6107 Cytochrome P450 3A7 CYP3A7 0.0282
1353 DNA topoisomerase 1 TOP1 0.0202
3552 DNA topoisomerase 1 topA 0.0202
588 Chromodomain-helicase-DNA-binding protein 1 CHD1 0.0192
1732 ATP-binding cassette sub-family G member 2 ABCG2 0.0189
6137 Multidrug resistance-associated protein 6 ABCC6 0.0163
4119 Cytochrome P450 2D6 CYP2D6 0.015
6024 Cytochrome P450 1A1 CYP1A1 0.0147
5718 Cytochrome P450 2A6 CYP2A6 0.0132
2539 Tubulin alpha-1 chain TUBA4A 0.0126
101 Potassium voltage-gated channel subfamily H member 2 KCNH2 0.012
161 Tubulin beta chain TUBB 0.0117
312 Tubulin beta chain TUB2 0.0117
723 Cytosolic phospholipase A2 PLA2G4A 0.0114
4757 Cytochrome P450 2C9 CYP2C9 0.0112
1898 Cytochrome P450 1B1 CYP1B1 0.0105
6016 Cytochrome P450 2C19 CYP2C19 0.0103
6178 UDP-glucuronosyltransferase 2B7 UGT2B7 0.0089
6148 Multidrug resistance-associated protein 7 ABCC10 0.0075
6013 Cytochrome P450 2E1 CYP2E1 0.0065
992 Protein tyrosine kinase 2 beta PTK2B 0.0064
4120 NADPH--cytochrome P450 reductase POR 0.0053
3947 Xanthine dehydrogenase/oxidase XDH 0.0045
6228 Nuclear receptor coactivator 1 NCOA1 0.0044
6241 Nuclear receptor coactivator 2 NCOA2 0.0043
869 Estrogen receptor beta ESR2 0.0041
776 Bile salt export pump ABCB11 0.0041
1709 Canalicular multispecific organic anion transporter 2 ABCC3 0.004
373 Transthyretin TTR 0.0038
6172 ATP-binding cassette sub-family B member 8, mitochondrial ABCB8 0.0036
136 Estrogen receptor ESR1 0.0035
908 Glutathione S-transferase theta-1 GSTT1 0.0032
337 NADH dehydrogenase [ubiquinone] iron-sulfur protein 7, mitochondrial NDUFS7 0.0029
214 NADH dehydrogenase [ubiquinone] iron-sulfur protein 3, mitochondrial NDUFS3 0.0029
803 NADH dehydrogenase [ubiquinone] iron-sulfur protein 2, mitochondrial NDUFS2 0.0029
6168 Solute carrier family 22 member 16 SLC22A16 0.0029
6861 Alcohol dehydrogenase [NADP+] AKR1A1 0.0026
904 Glutathione S-transferase P GSTP1 0.0025
6022 UDP-glucuronosyltransferase 1-1 UGT1A1 0.0023
5251 Carbonyl reductase [NADPH] 1 CBR1 0.0022
650 Aldo-keto reductase family 1 member C3 AKR1C3 0.0021
290 Prostaglandin G/H synthase 2 PTGS2 0.002
20 Prostaglandin G/H synthase 1 PTGS1 0.0019
2157 NAD(P)H dehydrogenase [quinone] 1 NQO1 0.0019
76 Nitric-oxide synthase, brain NOS1 0.0018
4924 Cytochrome P450 2C8 CYP2C8 0.0016
7 Nitric oxide synthase, inducible NOS2 0.0016
291 Nitric-oxide synthase, endothelial NOS3 0.0015
6030 Cytochrome P450 2B6 CYP2B6 0.0012
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