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Identification
NameGrepafloxacin
Accession NumberDB00365  (APRD01003)
TypeSmall Molecule
GroupsWithdrawn
Description

Grepafloxacin is an oral broad-spectrum quinoline antibacterial agent used to treat bacterial infections. Grepafloxacin was withdrawn in the United States due to its side effect of lengthening the QT interval on the electrocardiogram, leading to cardiac events and sudden death. [Wikipedia]

Structure
Thumb
SynonymsNot Available
External Identifiers Not Available
Approved Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Raxartablet200 mgoralOtsuka Pharma Gmbh1998-07-011999-10-27Canada
Approved Generic Prescription ProductsNot Available
Approved Over the Counter ProductsNot Available
Unapproved/Other Products Not Available
International BrandsNot Available
Brand mixturesNot Available
Salts
Name/CASStructureProperties
Grepafloxacin hydrochloride
ThumbNot applicableDBSALT000913
Categories
UNIIL1M1U2HC31
CAS number119914-60-2
WeightAverage: 359.3947
Monoisotopic: 359.16451979
Chemical FormulaC19H22FN3O3
InChI KeyInChIKey=AIJTTZAVMXIJGM-UHFFFAOYSA-N
InChI
InChI=1S/C19H22FN3O3/c1-10-8-22(6-5-21-10)15-7-14-16(11(2)17(15)20)18(24)13(19(25)26)9-23(14)12-3-4-12/h7,9-10,12,21H,3-6,8H2,1-2H3,(H,25,26)
IUPAC Name
1-cyclopropyl-6-fluoro-5-methyl-7-(3-methylpiperazin-1-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid
SMILES
CC1CN(CCN1)C1=C(F)C(C)=C2C(=O)C(=CN(C3CC3)C2=C1)C(O)=O
Taxonomy
DescriptionThis compound belongs to the class of organic compounds known as quinoline carboxylic acids. These are quinolines in which the quinoline ring system is substituted by a carboxyl group at one or more positions.
KingdomOrganic compounds
Super ClassOrganoheterocyclic compounds
ClassQuinolines and derivatives
Sub ClassQuinoline carboxylic acids
Direct ParentQuinoline carboxylic acids
Alternative Parents
Substituents
  • Quinoline-3-carboxylic acid
  • N-arylpiperazine
  • Fluoroquinolone
  • Dihydroquinolone
  • Aminoquinoline
  • Dihydroquinoline
  • Pyridine carboxylic acid or derivatives
  • Pyridine carboxylic acid
  • Dialkylarylamine
  • Fluorobenzene
  • Benzenoid
  • Pyridine
  • Piperazine
  • 1,4-diazinane
  • Aryl halide
  • Aryl fluoride
  • Heteroaromatic compound
  • Vinylogous amide
  • Tertiary amine
  • Azacycle
  • Secondary amine
  • Monocarboxylic acid or derivatives
  • Secondary aliphatic amine
  • Carboxylic acid
  • Carboxylic acid derivative
  • Hydrocarbon derivative
  • Organooxygen compound
  • Organonitrogen compound
  • Organofluoride
  • Organohalogen compound
  • Carbonyl group
  • Amine
  • Aromatic heteropolycyclic compound
Molecular FrameworkAromatic heteropolycyclic compounds
External DescriptorsNot Available
Pharmacology
IndicationFor treatment of adults with mild to moderate infections caused by susceptible strains of Haemophilus influenzae, Streptococcus pneumoniae, or Moraxella catarrhalis.
PharmacodynamicsGrepafloxacin has in vitro activity against a wide range of gram-positive and gram-negative aerobic microorganisms, as well as some atypical microorganisms.
Mechanism of actionGrepafloxacin exerts its antibacterial activity by inhibiting bacterial topoisomerase II (DNA gyrase) and topoisomerase IV, essential enzymes for duplication, transcription, and repair of bacterial DNA.
Related Articles
AbsorptionRapidly and extensively absorbed following oral administration. The absolute bioavailability is approximately 70%.
Volume of distributionNot Available
Protein binding50%
Metabolism

Primarily hepatic via CYP1A2 and CYP3A4. The major metabolite is a glucuronide conjugate; minor metabolites include sulfate conjugates and oxidative metabolites. The oxidative metabolites are formed mainly by the cytochrome P450 enzyme CYP1A2, while the cytochrome P450 enzyme CYP3A4 plays a minor role. The nonconjugated metabolites have little antimicrobial activity compared with the parent drug, and the conjugated metabolites have no antimicrobial activity

Route of eliminationNot Available
Half life15 ± 3 hours
ClearanceNot Available
ToxicityWithdrawn from the US market in 1999 due to associations with QTc prolongation and adverse cardiovascular events.
Affected organisms
  • Enteric bacteria and other eubacteria
  • Streptococcus pneumoniae
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.9886
Blood Brain Barrier-0.9855
Caco-2 permeable+0.5
P-glycoprotein substrateSubstrate0.8825
P-glycoprotein inhibitor INon-inhibitor0.9062
P-glycoprotein inhibitor IINon-inhibitor0.9228
Renal organic cation transporterNon-inhibitor0.7877
CYP450 2C9 substrateNon-substrate0.8299
CYP450 2D6 substrateNon-substrate0.9127
CYP450 3A4 substrateNon-substrate0.7079
CYP450 1A2 substrateNon-inhibitor0.8516
CYP450 2C9 inhibitorNon-inhibitor0.9197
CYP450 2D6 inhibitorNon-inhibitor0.9365
CYP450 2C19 inhibitorNon-inhibitor0.9064
CYP450 3A4 inhibitorNon-inhibitor0.8116
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.763
Ames testAMES toxic0.7309
CarcinogenicityNon-carcinogens0.8042
BiodegradationNot ready biodegradable1.0
Rat acute toxicity2.0923 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9009
hERG inhibition (predictor II)Non-inhibitor0.7785
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397 )
Pharmacoeconomics
Manufacturers
  • Otsuka pharmaceutical co ltd
Packagers
Dosage forms
FormRouteStrength
Tabletoral200 mg
PricesNot Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
CA1340492 No1999-04-132016-04-13Canada
US5563138 No1993-10-082013-10-08Us
Properties
StateSolid
Experimental Properties
PropertyValueSource
logP2.9Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.632 mg/mLALOGPS
logP-0.12ALOGPS
logP0.12ChemAxon
logS-2.8ALOGPS
pKa (Strongest Acidic)5.88ChemAxon
pKa (Strongest Basic)8.77ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count6ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area72.88 Å2ChemAxon
Rotatable Bond Count3ChemAxon
Refractivity97.4 m3·mol-1ChemAxon
Polarizability37.69 Å3ChemAxon
Number of Rings4ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Mass Spec (NIST)Not Available
Spectra
Spectrum TypeDescriptionSplash Key
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, PositiveNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, PositiveNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, PositiveNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, NegativeNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, NegativeNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, NegativeNot Available
References
Synthesis Reference

DrugSyn.org

US4920120
General ReferencesNot Available
External Links
ATC CodesJ01MA11
AHFS CodesNot Available
PDB EntriesNot Available
FDA labelNot Available
MSDSDownload (115 KB)
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. Stewart BA, Johnson AP, Woodford N: Relationship between mutations in parC and gyrA of clinical isolates of Streptococcus pneumoniae and resistance to ciprofloxacin and grepafloxacin. J Med Microbiol. 1999 Dec;48(12):1103-6. [PubMed:10591164 ]
  4. Jorgensen JH, Weigel LM, Ferraro MJ, Swenson JM, Tenover FC: Activities of newer fluoroquinolones against Streptococcus pneumoniae clinical isolates including those with mutations in the gyrA, parC, and parE loci. Antimicrob Agents Chemother. 1999 Feb;43(2):329-34. [PubMed:9925527 ]
  5. Griggs DJ, Marona H, Piddock LJ: Selection of moxifloxacin-resistant Staphylococcus aureus compared with five other fluoroquinolones. J Antimicrob Chemother. 2003 Jun;51(6):1403-7. Epub 2003 Apr 25. [PubMed:12716775 ]
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. Ernst EJ, Klepser ME, Petzold CR, Doern GV: Evaluation of survival and pharmacodynamic relationships for five fluoroquinolones in a neutropenic murine model of pneumococcal lung infection. Pharmacotherapy. 2002 Apr;22(4):463-70. [PubMed:11939681 ]
  4. Morris JE, Pan XS, Fisher LM: Grepafloxacin, a dimethyl derivative of ciprofloxacin, acts preferentially through gyrase in Streptococcus pneumoniae: role of the C-5 group in target specificity. Antimicrob Agents Chemother. 2002 Feb;46(2):582-5. [PubMed:11796384 ]
  5. Kawamura-Sato K, Hasegawa T, Torii K, Ito H, Ohta M: Prevalence of Ile-460-Val/ParE substitution in clinical Streptococcus pneumoniae isolates that were less susceptible to fluoroquinolones. Curr Microbiol. 2005 Jul;51(1):27-30. Epub 2005 May 31. [PubMed:15942701 ]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrate
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 unrelated compounds, including steroids, fatty acids, and xenobiotics. Most active in catalyzing 2-hydroxylation. Caffeine is metabolized primarily by cytochrome CYP1A2 in the liver through an initial N...
Gene Name:
CYP1A2
Uniprot ID:
P05177
Molecular Weight:
58293.76 Da
References
  1. Rodighiero V: Effects of liver disease on pharmacokinetics. An update. Clin Pharmacokinet. 1999 Nov;37(5):399-431. [PubMed:10589374 ]
  2. Bril F, Gonzalez CD, Di Girolamo G: Antimicrobial agents-associated with QT interval prolongation. Curr Drug Saf. 2010 Jan;5(1):85-92. [PubMed:20210724 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrate
General Function:
Vitamin d3 25-hydroxylase activity
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 performs a variety of oxidation reactions (e.g. caffeine 8-oxidation, omeprazole sulphoxidation, midazolam 1'-hydroxylation and midazolam 4-hydroxylation) of structurally unrelated compounds, including steroids, fatty acids, and xenobiot...
Gene Name:
CYP3A4
Uniprot ID:
P08684
Molecular Weight:
57342.67 Da
References
  1. Pal D, Mitra AK: MDR- and CYP3A4-mediated drug-drug interactions. J Neuroimmune Pharmacol. 2006 Sep;1(3):323-39. Epub 2006 Aug 2. [PubMed:18040809 ]
  2. Owens RC Jr: QT prolongation with antimicrobial agents: understanding the significance. Drugs. 2004;64(10):1091-124. [PubMed:15139788 ]

Transporters

Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrateinhibitor
General Function:
Xenobiotic-transporting atpase activity
Specific Function:
Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells.
Gene Name:
ABCB1
Uniprot ID:
P08183
Molecular Weight:
141477.255 Da
References
  1. Yamaguchi H, Yano I, Hashimoto Y, Inui KI: Secretory mechanisms of grepafloxacin and levofloxacin in the human intestinal cell line caco-2. J Pharmacol Exp Ther. 2000 Oct;295(1):360-6. [PubMed:10992002 ]
  2. Naruhashi K, Tamai I, Inoue N, Muraoka H, Sai Y, Suzuki N, Tsuji A: Active intestinal secretion of new quinolone antimicrobials and the partial contribution of P-glycoprotein. J Pharm Pharmacol. 2001 May;53(5):699-709. [PubMed:11370709 ]
  3. Yamaguchi H, Yano I, Saito H, Inui K: Effect of cisplatin-induced acute renal failure on bioavailability and intestinal secretion of quinolone antibacterial drugs in rats. Pharm Res. 2004 Feb;21(2):330-8. [PubMed:15032316 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrate
General Function:
Transporter activity
Specific Function:
Mediates export of organic anions and drugs from the cytoplasm. Mediates ATP-dependent transport of glutathione and glutathione conjugates, leukotriene C4, estradiol-17-beta-o-glucuronide, methotrexate, antiviral drugs and other xenobiotics. Confers resistance to anticancer drugs. Hydrolyzes ATP with low efficiency.
Gene Name:
ABCC1
Uniprot ID:
P33527
Molecular Weight:
171589.5 Da
References
  1. Tamai I, Yamashita J, Kido Y, Ohnari A, Sai Y, Shima Y, Naruhashi K, Koizumi S, Tsuji A: Limited distribution of new quinolone antibacterial agents into brain caused by multiple efflux transporters at the blood-brain barrier. J Pharmacol Exp Ther. 2000 Oct;295(1):146-52. [PubMed:10991972 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrate
General Function:
Sodium-independent organic anion transmembrane transporter activity
Specific Function:
Involved in the renal elimination of endogenous and exogenous organic anions. Functions as organic anion exchanger when the uptake of one molecule of organic anion is coupled with an efflux of one molecule of endogenous dicarboxylic acid (glutarate, ketoglutarate, etc). Mediates the sodium-independent uptake of 2,3-dimercapto-1-propanesulfonic acid (DMPS) (By similarity). Mediates the sodium-in...
Gene Name:
SLC22A6
Uniprot ID:
Q4U2R8
Molecular Weight:
61815.78 Da
References
  1. Uwai Y, Okuda M, Takami K, Hashimoto Y, Inui K: Functional characterization of the rat multispecific organic anion transporter OAT1 mediating basolateral uptake of anionic drugs in the kidney. FEBS Lett. 1998 Nov 6;438(3):321-4. [PubMed:9827570 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
inhibitor
General Function:
Quaternary ammonium group transmembrane transporter activity
Specific Function:
Mediates tubular uptake of organic compounds from circulation. Mediates the influx of agmatine, dopamine, noradrenaline (norepinephrine), serotonin, choline, famotidine, ranitidine, histamin, creatinine, amantadine, memantine, acriflavine, 4-[4-(dimethylamino)-styryl]-N-methylpyridinium ASP, amiloride, metformin, N-1-methylnicotinamide (NMN), tetraethylammonium (TEA), 1-methyl-4-phenylpyridiniu...
Gene Name:
SLC22A2
Uniprot ID:
O15244
Molecular Weight:
62579.99 Da
References
  1. Urakami Y, Akazawa M, Saito H, Okuda M, Inui K: cDNA cloning, functional characterization, and tissue distribution of an alternatively spliced variant of organic cation transporter hOCT2 predominantly expressed in the human kidney. J Am Soc Nephrol. 2002 Jul;13(7):1703-10. [PubMed:12089365 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
inhibitor
General Function:
Symporter activity
Specific Function:
Sodium-ion dependent, high affinity carnitine transporter. Involved in the active cellular uptake of carnitine. Transports one sodium ion with one molecule of carnitine. Also transports organic cations such as tetraethylammonium (TEA) without the involvement of sodium. Also relative uptake activity ratio of carnitine to TEA is 11.3.
Gene Name:
SLC22A5
Uniprot ID:
O76082
Molecular Weight:
62751.08 Da
References
  1. Ohashi R, Tamai I, Yabuuchi H, Nezu JI, Oku A, Sai Y, Shimane M, Tsuji A: Na(+)-dependent carnitine transport by organic cation transporter (OCTN2): its pharmacological and toxicological relevance. J Pharmacol Exp Ther. 1999 Nov;291(2):778-84. [PubMed:10525100 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
inhibitor
General Function:
Organic anion transmembrane transporter activity
Specific Function:
Mediates hepatobiliary excretion of numerous organic anions. May function as a cellular cisplatin transporter.
Gene Name:
ABCC2
Uniprot ID:
Q92887
Molecular Weight:
174205.64 Da
References
  1. Sasabe H, Tsuji A, Sugiyama Y: Carrier-mediated mechanism for the biliary excretion of the quinolone antibiotic grepafloxacin and its glucuronide in rats. J Pharmacol Exp Ther. 1998 Mar;284(3):1033-9. [PubMed:9495864 ]
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Drug created on June 13, 2005 07:24 / Updated on August 17, 2016 12:23