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Identification
NameFloxuridine
Accession NumberDB00322  (APRD00692)
Typesmall molecule
Groupsapproved
Description

An antineoplastic antimetabolite that is metabolized to fluorouracil when administered by rapid injection. Floxuridine is available as a sterile, nonpyrogenic, lyophilized powder for reconstitution. When administered by slow, continuous, intra-arterial infusion, it is converted to floxuridine monophosphate. It has been used to treat hepatic metastases of gastrointestinal adenocarcinomas and for palliation in malignant neoplasms of the liver and gastrointestinal tract. [PubChem]

Structure
Thumb
Synonyms
SynonymLanguageCode
DeoxyfluorouridineNot AvailableNot Available
FloxiridinaSpanishINN
FloxuridinGermanINN
FloxuridineNot AvailableUSAN, USP 34
FloxuridinumLatinINN
FluorodeoxyuridineNot AvailableNot Available
Fluoruridine DeoxyriboseNot AvailableNot Available
FUDRNot AvailableIS
SaltsNot Available
Brand names
NameCompany
FloxuridineAPP
FUDRMayne
Brand mixturesNot Available
Categories
CAS number50-91-9
WeightAverage: 246.1924
Monoisotopic: 246.065199677
Chemical FormulaC9H11FN2O5
InChI KeyInChIKey=ODKNJVUHOIMIIZ-RRKCRQDMSA-N
InChI
InChI=1S/C9H11FN2O5/c10-4-2-12(9(16)11-8(4)15)7-1-5(14)6(3-13)17-7/h2,5-7,13-14H,1,3H2,(H,11,15,16)/t5-,6+,7+/m0/s1
IUPAC Name
5-fluoro-1-[(2R,4S,5R)-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-1,2,3,4-tetrahydropyrimidine-2,4-dione
SMILES
OC[C@H]1O[C@H](C[C@@H]1O)N1C=C(F)C(=O)NC1=O
Mass Specshow(9.43 KB)
Taxonomy
KingdomOrganic Compounds
SuperclassOrganooxygen Compounds
ClassCarbohydrates and Carbohydrate Conjugates
SubclassGlycosyl Compounds
Direct parentPyrimidine 2'-deoxyribonucleosides and Analogues
Alternative parentsPentoses; Halopyrimidines; Pyrimidones; Aryl Fluorides; Hydropyrimidines; Tetrahydrofurans; Oxolanes; Secondary Alcohols; Polyamines; Primary Alcohols; Ethers; Organofluorides
Substituentspentose monosaccharide; pyrimidone; halopyrimidine; hydropyrimidine; aryl halide; monosaccharide; pyrimidine; aryl fluoride; tetrahydrofuran; oxolane; secondary alcohol; ether; polyamine; primary alcohol; organohalogen; alcohol; amine; organonitrogen compound; organofluoride
Classification descriptionThis compound belongs to the pyrimidine 2'-deoxyribonucleosides and analogues. These are compounds consisting of a pyrimidine linked to a ribose which lacks an hydroxyl group at position 2.
Pharmacology
IndicationFor palliative management of gastrointestinal adenocarcinoma metastatic to the liver, when given by continuous regional intra-arterial infusion in carefully selected patients who are considered incurable by surgery or other means. Also for the palliative management of liver cancer (usually administered by hepatic intra-arterial infusion).
PharmacodynamicsFloxuridine is a pyrimidine analog that acts as an inhibitor of the S-phase of cell division. This selectively kills rapidly dividing cells. Floxuridine is an anti-metabolite. Anti-metabolites masquerade as pyramidine-like molecules which prevents normal pyrimidines from being incorporated into DNA during the S phase of the cell cycle. Flurouracil (the end-product of catabolism of floxuridine) blocks an enzyme which converts cytosine nucleosides into the deoxy derivative. In addition, DNA synthesis is further inhibited because fluoruracil blocks the incorporation of the thymdine nucleotide into the DNA strand.
Mechanism of actionFloxuridine is rapidly catabolized to 5-fluorouracil, which is the active form of the drug. The primary effect is interference with DNA synthesis and to a lesser extent, inhibition of RNA formation through the drug's incorporation into RNA, thus leading to the production of fraudulent RNA. Fluorouracil also inhibits uracil riboside phophorylase, which prevents the utilization of preformed uracil in RNA synthesis. As well, the monophosphate of floxuridine, 5-fluoro-2'-deoxyuridine-5'-phosphate (FUDR-MP) inhibits the enzyme thymidylate synthetase. This leads to the inhibition of methylation of deoxyuridylic acid to thymidylic acid, thus interfering with DNA synthesis.
AbsorptionNot Available
Volume of distributionNot Available
Protein bindingNot Available
Metabolism

Hepatic.

SubstrateEnzymesProduct
Floxuridine
5-fluorouracilDetails
Floxuridine
    5,6-Dihydro-5-fluorouracilDetails
    Floxuridine
      alpha-Fluoro-beta-alanineDetails
      Floxuridine
        Fluoro-beta-ureidopropionateDetails
        Route of eliminationThe drug is excreted intact and as urea, fluorouracil, a-fluoro-bureidopropionic acid, dihydrofluorouracil, a-fluoro-b-guanidopropionic acid and a-fluoro-b-alanine in the urine; it is also expired as respiratory carbon dioxide.
        Half lifeNot Available
        ClearanceNot Available
        ToxicityOral, rat LD50: 215 mg/kg. Signs of overdose include nausea, vomiting, diarrhea, gastrointestinal ulceration and bleeding, and bone marrow depression (including thrombocytopenia, leukopenia and agranulocytosis).
        Affected organisms
        • Humans and other mammals
        PathwaysNot Available
        SNP Mediated EffectsNot Available
        SNP Mediated Adverse Drug ReactionsNot Available
        ADMET
        Predicted ADMET features
        Property Value Probability
        Human Intestinal Absorption + 0.9589
        Blood Brain Barrier + 0.768
        Caco-2 permeable - 0.8988
        P-glycoprotein substrate Non-substrate 0.7043
        P-glycoprotein inhibitor I Non-inhibitor 0.854
        P-glycoprotein inhibitor II Non-inhibitor 0.888
        Renal organic cation transporter Non-inhibitor 0.8956
        CYP450 2C9 substrate Non-substrate 0.805
        CYP450 2D6 substrate Non-substrate 0.8668
        CYP450 3A4 substrate Non-substrate 0.5459
        CYP450 1A2 substrate Non-inhibitor 0.9125
        CYP450 2C9 substrate Non-inhibitor 0.9159
        CYP450 2D6 substrate Non-inhibitor 0.9235
        CYP450 2C19 substrate Non-inhibitor 0.9162
        CYP450 3A4 substrate Non-inhibitor 0.8926
        CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.8378
        Ames test Non AMES toxic 0.6041
        Carcinogenicity Non-carcinogens 0.7542
        Biodegradation Not ready biodegradable 0.9528
        Rat acute toxicity 2.5247 LD50, mol/kg Not applicable
        hERG inhibition (predictor I) Weak inhibitor 0.9508
        hERG inhibition (predictor II) Non-inhibitor 0.7771
        Pharmacoeconomics
        Manufacturers
        • App pharmaceuticals llc
        • Bedford laboratories div ben venue laboratories inc
        • Hospira inc
        Packagers
        Dosage forms
        FormRouteStrength
        Powder, for solutionIntra-arterial
        Prices
        Unit descriptionCostUnit
        Floxuridine 500 mg vial144.0USDvial
        Fudr 500 mg vial121.06USDvial
        DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
        PatentsNot Available
        Properties
        Statesolid
        Experimental Properties
        PropertyValueSource
        melting point150.5 °CPhysProp
        water solubility1.19E+004 mg/LNot Available
        logP-1.16HANSCH,C ET AL. (1995)
        pKa7.44SANGSTER (1994)
        Predicted Properties
        PropertyValueSource
        water solubility4.08e+01 g/lALOGPS
        logP-1.1ALOGPS
        logP-1.3ChemAxon
        logS-0.78ALOGPS
        pKa (strongest acidic)7.68ChemAxon
        pKa (strongest basic)-3ChemAxon
        physiological charge0ChemAxon
        hydrogen acceptor count5ChemAxon
        hydrogen donor count3ChemAxon
        polar surface area99.1ChemAxon
        rotatable bond count2ChemAxon
        refractivity51.26ChemAxon
        polarizability20.78ChemAxon
        number of rings2ChemAxon
        bioavailability1ChemAxon
        rule of fiveYesChemAxon
        Ghose filterNoChemAxon
        Veber's ruleNoChemAxon
        MDDR-like ruleNoChemAxon
        Spectra
        SpectraNot Available
        References
        Synthesis ReferenceNot Available
        General ReferenceNot Available
        External Links
        ResourceLink
        KEGG DrugD04197
        KEGG CompoundC11736
        PubChem Compound5790
        PubChem Substance46508645
        ChemSpider5586
        BindingDB50042595
        ChEBI60761
        ChEMBLCHEMBL917
        Therapeutic Targets DatabaseDAP001245
        PharmGKBPA449652
        RxListhttp://www.rxlist.com/cgi/generic2/floxuridine.htm
        Drugs.comhttp://www.drugs.com/cdi/floxuridine.html
        WikipediaFloxuridine
        ATC CodesNot Available
        AHFS CodesNot Available
        PDB EntriesNot Available
        FDA labelNot Available
        MSDSshow(40.5 KB)
        Interactions
        Drug Interactions
        Drug
        TamoxifenFloxuridine may reduce clearance rate of Tamoxifen. Monitor for changes in therapeutic/adverse effects of Tamoxifen if Floxiridine is initiated, discontinued or dose changed.
        TolbutamideFloxuridine, a strong CYP2C9 inhibitor, may decrease the metabolism and clearance of Tolbutamide, a CYP2C9 substrate. Consider alternate therapy or monitor for changes in Tolbutamide therapeutic and adverse effects if Floxuridine is initiated, discontinued or dose changed.
        TorasemideFloxuridine, a strong CYP2C9 inhibitor, may increase the serum concentration of Torasemide, a CYP2C9 substrate, by decreasing Torasemide metabolism and clearance. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of Torasemide if Floxuridine is initiated, discontinued or dose changed.
        TrastuzumabTrastuzumab may increase the risk of neutropenia and anemia. Monitor closely for signs and symptoms of adverse events.
        TrimethoprimThe strong CYP2C9 inhibitor, Floxuridine, may decrease the metabolism and clearance of Trimethoprim, a CYP2C9 substrate. Consider alternate therapy or monitor for changes in therapeutic and adverse effects of Trimethoprim if Floxuridine is initiated, discontinued or dose changed.
        VoriconazoleFloxuridine, a strong CYP2C9 inhibitor, may increase the serum concentration of voriconazole by decreasing its metabolism. Monitor for changes in the therapeutic and adverse effects of voriconazole if floxuridine is initiated, discontinued or dose changed.
        WarfarinFloxuridine, a strong CYP2C9 inhibitor, may decrease the metabolism of warfarin. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of warfarin if floxuridine is initiated, discontinued or dose changed.
        ZafirlukastFloxuridine, a strong CYP2C9 inhibitor, may decrease the metabolism and clearance of zafirlukast. Consider alternate therapy or monitor for changes in zafirlukast therapeutic and adverse effects if floxuridine is initiated, discontinued or dose changed.
        Food InteractionsNot Available

        1. Thymidylate synthase

        Kind: protein

        Organism: Human

        Pharmacological action: yes

        Components

        Name UniProt ID Details
        Thymidylate synthase P04818 Details

        References:

        1. Ferguson PJ, Collins O, Dean NM, DeMoor J, Li CS, Vincent MD, Koropatnick J: Antisense down-regulation of thymidylate synthase to suppress growth and enhance cytotoxicity of 5-FUdR, 5-FU and Tomudex in HeLa cells. Br J Pharmacol. 1999 Aug;127(8):1777-86. Pubmed
        2. Kubota T: [Theoretical basis for low-dose CDDP/5-FU therapy] Gan To Kagaku Ryoho. 1999 Oct;26(11):1536-41. Pubmed
        3. Kuwa K, Sakamoto S, Sassa S, Yoshimura S, Maemura M, Nakayama T: Effects of long-term administration of UFT plus leucovorin on colorectal tumors induced with 1,2-dimethylhydrazine in rats. Anticancer Res. 1999 Nov-Dec;19(6B):5139-42. Pubmed
        4. Kuwa K, Sakamoto S, Mitamura T, Kudo H, Suzuki S, Fukushima M: Effects of a low dose leucovorin with 5-fluorouracil derivative on colorectal tumors induced with 1,2-dimethylhydrazine in rats. Anticancer Res. 1999 Nov-Dec;19(6B):5143-8. Pubmed
        5. Murakami Y, Kazuno H, Emura T, Tsujimoto H, Suzuki N, Fukushima M: Different mechanisms of acquired resistance to fluorinated pyrimidines in human colorectal cancer cells. Int J Oncol. 2000 Aug;17(2):277-83. Pubmed

        1. Thymidine phosphorylase

        Kind: protein

        Organism: Human

        Pharmacological action: unknown

        Actions: substrate

        Components

        Name UniProt ID Details
        Thymidine phosphorylase P19971 Details

        References:

        1. BIRNIE GD, KROEGER H, HEIDELBERGER C: STUDIES OF FLUORINATED PYRIMIDINES. XVIII. THE DEGRADATION OF 5-FLUORO-2’-DEOXYURIDINE AND RELATED COMPOUNDS BY NUCLEOSIDE PHOSPHORYLASE. Biochemistry. 1963 May-Jun;2:566-72. Pubmed
        2. Tsume Y, Hilfinger JM, Amidon GL: Enhanced cancer cell growth inhibition by dipeptide prodrugs of floxuridine: increased transporter affinity and metabolic stability. Mol Pharm. 2008 Sep-Oct;5(5):717-27. doi: 10.1021/mp800008c. Epub 2008 Jul 25. Pubmed

        Comments
        Drug created on June 13, 2005 07:24 / Updated on September 16, 2013 17:09