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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
1-(2-Deoxy-beta-D-ribofuranosyl)-5-fluorouracilNot AvailableNot Available
1-beta-D-2'-Deoxyribofuranosyl-5-flurouracilNot AvailableNot Available
1beta-D-2'-Deoxyribofuranosyl-5-flurouracilNot AvailableNot Available
2'-Deoxy-5-fluorouridineNot AvailableNot Available
5-Fluoro-2-desoxyuridineNot AvailableNot Available
5-FluorodeoxyuridineNot AvailableNot Available
5-Fluorouracil 2'-deoxyribosideNot AvailableNot Available
5-Fluorouracil deoxyribosideNot AvailableNot Available
5FDUNot AvailableNot Available
beta-5-Fluoro-2'-deoxyuridineNot AvailableNot Available
DeoxyfluorouridineNot AvailableNot Available
FdUNot AvailableNot Available
FloxiridinaSpanishINN
FloxuridinGermanINN
FloxuridineNot AvailableUSAN, USP 34
FloxuridinumLatinINN
FluorodeoxyuridineNot AvailableNot Available
Fluoruridine DeoxyriboseNot AvailableNot Available
FUDRNot AvailableIS
Prescription ProductsNot Available
Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Floxuridineinjection, powder, lyophilized, for solution500 mg/5mLintra-arterialAPP Pharmaceuticals, LLC2001-03-15Not AvailableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Over the Counter ProductsNot Available
International Brands
NameCompany
FUDRMayne
Brand mixturesNot Available
SaltsNot Available
Categories
CAS number50-91-9
WeightAverage: 246.1924
Monoisotopic: 246.065199677
Chemical FormulaC9H11FN2O5
InChI KeyODKNJVUHOIMIIZ-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
Taxonomy
DescriptionThis compound belongs to the class of organic compounds known as pyrimidine 2'-deoxyribonucleosides. These are compounds consisting of a pyrimidine linked to a ribose which lacks a hydroxyl group at position 2.
KingdomOrganic compounds
Super ClassNucleosides, nucleotides, and analogues
ClassPyrimidine nucleosides
Sub ClassPyrimidine 2'-deoxyribonucleosides
Direct ParentPyrimidine 2'-deoxyribonucleosides
Alternative Parents
Substituents
  • Pyrimidine 2'-deoxyribonucleoside
  • Pyrimidone
  • Halopyrimidine
  • Pyrimidine
  • Hydropyrimidine
  • Aryl halide
  • Aryl fluoride
  • Heteroaromatic compound
  • Vinylogous amide
  • Oxolane
  • Urea
  • Secondary alcohol
  • Lactam
  • Oxacycle
  • Azacycle
  • Organoheterocyclic compound
  • Hydrocarbon derivative
  • Primary alcohol
  • Organooxygen compound
  • Organonitrogen compound
  • Organofluoride
  • Organohalogen compound
  • Alcohol
  • Aromatic heteromonocyclic compound
Molecular FrameworkAromatic heteromonocyclic compounds
External Descriptors
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
Not Available
5,6-Dihydro-5-fluorouracilDetails
Floxuridine
Not Available
alpha-Fluoro-beta-alanineDetails
Floxuridine
Not Available
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
PropertyValueProbability
Human Intestinal Absorption+0.9589
Blood Brain Barrier+0.768
Caco-2 permeable-0.8988
P-glycoprotein substrateNon-substrate0.7043
P-glycoprotein inhibitor INon-inhibitor0.854
P-glycoprotein inhibitor IINon-inhibitor0.888
Renal organic cation transporterNon-inhibitor0.8956
CYP450 2C9 substrateNon-substrate0.805
CYP450 2D6 substrateNon-substrate0.8668
CYP450 3A4 substrateNon-substrate0.5459
CYP450 1A2 substrateNon-inhibitor0.9125
CYP450 2C9 substrateNon-inhibitor0.9159
CYP450 2D6 substrateNon-inhibitor0.9235
CYP450 2C19 substrateNon-inhibitor0.9162
CYP450 3A4 substrateNon-inhibitor0.8926
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.8378
Ames testNon AMES toxic0.6041
CarcinogenicityNon-carcinogens0.7542
BiodegradationNot ready biodegradable0.9528
Rat acute toxicity2.5247 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9508
hERG inhibition (predictor II)Non-inhibitor0.7771
Pharmacoeconomics
Manufacturers
  • App pharmaceuticals llc
  • Bedford laboratories div ben venue laboratories inc
  • Hospira inc
Packagers
Dosage forms
FormRouteStrength
Injection, powder, lyophilized, for solutionintra-arterial500 mg/5mL
Prices
Unit descriptionCostUnit
Floxuridine 500 mg vial144.0USD vial
Fudr 500 mg vial121.06USD vial
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 Solubility40.8 mg/mLALOGPS
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 Area99.1 Å2ChemAxon
Rotatable Bond Count2ChemAxon
Refractivity51.26 m3·mol-1ChemAxon
Polarizability20.78 Å3ChemAxon
Number of Rings2ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Mass Spec (NIST)Download (9.43 KB)
SpectraNot Available
References
Synthesis Reference

U.S. Patent 3,041,335.

General ReferenceNot Available
External Links
ATC CodesNot Available
AHFS CodesNot Available
PDB EntriesNot Available
FDA labelNot Available
MSDSDownload (40.5 KB)
Interactions
Drug Interactions
Drug
BosentanCYP2C9 Inhibitors (Strong) may increase the serum concentration of Bosentan.
CarvedilolCYP2C9 Inhibitors (Strong) may increase the serum concentration of Carvedilol. Specifically, concentrations of the S-carvedilol enantiomer may be increased.
CimetidineMay increase serum concentrations of the active metabolite(s) of Floxuridine. Specifically, concentrations of fluorouracil may be increased.
ClozapineMyelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for agranulocytosis may be increased.
DenosumabMay enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased.
DronabinolCYP2C9 Inhibitors (Strong) may increase the serum concentration of Dronabinol.
FosphenytoinFloxuridine may increase the serum concentration of Fosphenytoin.
LacosamideCYP2C9 Inhibitors (Strong) may increase the serum concentration of Lacosamide.
LeflunomideImmunosuppressants may enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased.
NatalizumabImmunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased.
OspemifeneCYP2C9 Inhibitors (Strong) may increase the serum concentration of Ospemifene.
PhenytoinMay increase the serum concentration of Phenytoin.
PimecrolimusMay enhance the adverse/toxic effect of Immunosuppressants.
RoflumilastMay enhance the immunosuppressive effect of Immunosuppressants.
Sipuleucel-TImmunosuppressants may diminish the therapeutic effect of Sipuleucel-T.
TofacitinibImmunosuppressants may enhance the immunosuppressive effect of Tofacitinib.
TrastuzumabMay enhance the neutropenic effect of Immunosuppressants.
Food InteractionsNot Available

Targets

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

Enzymes

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

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Drug created on June 13, 2005 07:24 / Updated on April 22, 2014 15:55