Identification

Name
Floxuridine
Accession Number
DB00322  (APRD00692)
Type
Small Molecule
Groups
Approved
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
  • 1-(2-Deoxy-beta-D-ribofuranosyl)-5-fluorouracil
  • 1-beta-D-2'-Deoxyribofuranosyl-5-flurouracil
  • 1beta-D-2'-Deoxyribofuranosyl-5-flurouracil
  • 2'-Deoxy-5-fluorouridine
  • 5-Fluoro-2-desoxyuridine
  • 5-Fluorodeoxyuridine
  • 5-Fluorouracil 2'-deoxyriboside
  • 5-Fluorouracil deoxyriboside
  • 5FDU
  • beta-5-Fluoro-2'-deoxyuridine
  • Deoxyfluorouridine
  • FdU
  • Floxiridina
  • Floxuridin
  • Floxuridine
  • Floxuridinum
  • Fluorodeoxyuridine
  • Fluoruridine Deoxyribose
External IDs
NSC-27640
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
FdurInjection, powder, lyophilized, for solution500 mg/5mLIntra-arterialHospira Worldwide, Inc.1970-12-182009-04-05Us
Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
FloxuridineInjection, powder, lyophilized, for solution100 mg/1mLIntra-arterialBedford Pharmaceuticals2000-10-162012-08-31Us
FloxuridineInjection, powder, lyophilized, for solution100 mg/1mLIntra-arterialWest-Ward Pharmaceuticals Corp2018-02-15Not applicableUs
FloxuridineInjection, powder, lyophilized, for solution500 mg/5mLIntra-arterialFresenius Kabi2001-03-15Not applicableUs
International/Other Brands
FUDR (Mayne)
Categories
UNII
039LU44I5M
CAS number
50-91-9
Weight
Average: 246.1924
Monoisotopic: 246.065199677
Chemical Formula
C9H11FN2O5
InChI Key
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

Pharmacology

Indication

For 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).

Associated Conditions
Pharmacodynamics

Floxuridine 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 action

Floxuridine 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.

TargetActionsOrganism
AThymidylate synthaseNot AvailableHuman
Absorption
Not Available
Volume of distribution
Not Available
Protein binding
Not Available
Metabolism

Hepatic.

Route of elimination

The 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 life
Not Available
Clearance
Not Available
Toxicity

Oral, 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
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
(S)-WarfarinThe metabolism of (S)-Warfarin can be decreased when combined with Floxuridine.
2-MethoxyethanolThe risk or severity of adverse effects can be increased when Floxuridine is combined with 2-Methoxyethanol.
9-(N-methyl-L-isoleucine)-cyclosporin AThe risk or severity of adverse effects can be increased when Floxuridine is combined with 9-(N-methyl-L-isoleucine)-cyclosporin A.
AbacavirFloxuridine may decrease the excretion rate of Abacavir which could result in a higher serum level.
AbataceptThe risk or severity of adverse effects can be increased when Abatacept is combined with Floxuridine.
AbetimusThe risk or severity of adverse effects can be increased when Floxuridine is combined with Abetimus.
AcarboseAcarbose may decrease the excretion rate of Floxuridine which could result in a higher serum level.
AceclofenacAceclofenac may decrease the excretion rate of Floxuridine which could result in a higher serum level.
AcemetacinAcemetacin may decrease the excretion rate of Floxuridine which could result in a higher serum level.
AcenocoumarolThe metabolism of Acenocoumarol can be decreased when combined with Floxuridine.
Food Interactions
Not Available

References

Synthesis Reference

U.S. Patent 3,041,335.

General References
Not Available
External Links
Human Metabolome Database
HMDB0014467
KEGG Drug
D04197
KEGG Compound
C11736
PubChem Compound
5790
PubChem Substance
46508645
ChemSpider
5586
BindingDB
50340678
ChEBI
60761
ChEMBL
CHEMBL917
Therapeutic Targets Database
DAP001245
PharmGKB
PA449652
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Floxuridine
MSDS
Download (40.5 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1Active Not RecruitingTreatmentCholangiocellular Carcinoma) (ICC) / Cholangiolar Carcinoma / Intrahepatic Cholangiocarcinoma / Peripheral Cholangiocarcinoma1
1Active Not RecruitingTreatmentColorectal Cancers / Metastatic Cancers1
1Active Not RecruitingTreatmentMalignant Neoplasm of Colon / Rectal Carcinoma1
1Active Not RecruitingTreatmentStage IV Fallopian Tube Cancer / Stage IV Fallopian Tube Cancer AJCC v6 and v7 / Stage IV Ovarian Cancer / Stage IV Ovarian Cancer AJCC v6 and v7 / Stage IV Primary Peritoneal Cancer / Stage IV Primary Peritoneal Cancer AJCC v71
1CompletedTreatmentCancers1
1CompletedTreatmentColorectal Cancers / Metastatic Cancers1
1CompletedTreatmentNeoplasms1
1CompletedTreatmentNeoplasms Metastasis / Neoplasms, Colorectal / Neoplasms, Hepatic1
1RecruitingTreatmentCholangiocarcinomas / Neoplasms, Hepatic1
1, 2CompletedTreatmentHepatic Metastases / Metastatic Colon Cancer / Recurrent Colon Cancer / Recurrent Rectal Cancer / Stage IV Rectal Cancer1
2Active Not RecruitingTreatmentColorectal Cancers / Metastatic Cancers1
2Active Not RecruitingTreatmentLiver Cancer1
2CompletedTreatmentAdenocarcinoma of the Colon / Adenocarcinoma of the Rectum / Hepatic Metastases / Metastatic Colon Cancer / Recurrent Colon Cancer / Recurrent Rectal Cancer / Stage IV Rectal Cancer1
2CompletedTreatmentCancer of the Ovary / Carcinoid tumour of the gastrointestinal tract / Colorectal Cancers / Gastrointestinal Stromal Tumors / Malignant Neoplasm of Stomach / Peritoneal Cavity Cancer / Small Intestine Cancer1
2CompletedTreatmentColorectal Cancers / Metastatic Cancers4
2CompletedTreatmentEsophageal Cancers1
2CompletedTreatmentEsophageal Cancers / Malignant Neoplasm of Stomach1
2CompletedTreatmentGastric Adenocarcinoma / Malignant Neoplasm of Stomach1
2CompletedTreatmentHepatic Metastases / Metastatic Colon Cancer / Recurrent Colon Cancer / Recurrent Rectal Cancer / Stage IV Rectal Cancer1
2CompletedTreatmentHepatic neoplasms malignant1
2CompletedTreatmentMalignant Neoplasm of Stomach3
2Not Yet RecruitingTreatmentCholangiocarcinomas / Colorectal Cancers1
2RecruitingTreatmentCholangiocellular Carcinoma / Cholangiolar Carcinoma / Intrahepatic Cholangiocarcinoma / Peripheral Cholangiocarcinoma1
2RecruitingTreatmentColo-rectal Cancer / Hepatic Metastases1
2RecruitingTreatmentColorectal Adenocarcinoma Metastatic to the Liver1
2TerminatedTreatmentColorectal Cancers1
2TerminatedTreatmentEsophageal Cancers / Gastric Adenocarcinoma / Malignant Neoplasm of Stomach1
2TerminatedTreatmentMalignant Neoplasm of Stomach1
2Unknown StatusTreatmentColorectal Cancers / Metastatic Cancers1
3CompletedTreatmentColorectal Cancers / Metastatic Cancers2
3Not Yet RecruitingTreatmentHepatic Metastases / Metastatic Colorectal Cancers1
3RecruitingTreatmentColorectal Cancers / HAI / Hepatic Metastases1
3RecruitingTreatmentColorectal Cancers / Metastasis1
3RecruitingTreatmentMetastatic Colorectal Cancers1
3TerminatedTreatmentColorectal Cancers / Metastatic Cancers1

Pharmacoeconomics

Manufacturers
  • App pharmaceuticals llc
  • Bedford laboratories div ben venue laboratories inc
  • Hospira inc
Packagers
  • APP Pharmaceuticals
  • Bedford Labs
  • Ben Venue Laboratories Inc.
  • Ethex Corp.
  • Hospira Inc.
Dosage forms
FormRouteStrength
Injection, powder, lyophilized, for solutionIntra-arterial500 mg/5mL
Injection, powder, lyophilized, for solutionIntra-arterial100 mg/1mL
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.
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)150.5 °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-1.2ALOGPS
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 FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
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 inhibitorNon-inhibitor0.9159
CYP450 2D6 inhibitorNon-inhibitor0.9235
CYP450 2C19 inhibitorNon-inhibitor0.9162
CYP450 3A4 inhibitorNon-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
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Download (9.43 KB)
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
GC-MS Spectrum - EI-BGC-MSsplash10-00lr-9600000000-155a97133c7827d2a1ce
GC-MS Spectrum - CI-BGC-MSsplash10-001i-3900000000-44f00976f508bab47f36
GC-MS Spectrum - CI-BGC-MSsplash10-00kb-2910000000-2efae68e874a5fdba01c
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 pyrimidine 2'-deoxyribonucleosides. These are compounds consisting of a pyrimidine linked to a ribose which lacks a hydroxyl group at position 2.
Kingdom
Organic compounds
Super Class
Nucleosides, nucleotides, and analogues
Class
Pyrimidine nucleosides
Sub Class
Pyrimidine 2'-deoxyribonucleosides
Direct Parent
Pyrimidine 2'-deoxyribonucleosides
Alternative Parents
Pyrimidones / Halopyrimidines / Hydroxypyrimidines / Aryl fluorides / Hydropyrimidines / Tetrahydrofurans / Heteroaromatic compounds / Secondary alcohols / Oxacyclic compounds / Azacyclic compounds
show 6 more
Substituents
Pyrimidine 2'-deoxyribonucleoside / Halopyrimidine / Hydroxypyrimidine / Pyrimidone / Aryl fluoride / Aryl halide / Hydropyrimidine / Pyrimidine / Heteroaromatic compound / Tetrahydrofuran
show 16 more
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
organofluorine compound, nucleoside analogue, pyrimidine 2'-deoxyribonucleoside (CHEBI:60761)

Targets

Kind
Protein
Organism
Human
Pharmacological action
Yes
General Function
Thymidylate synthase activity
Specific Function
Contributes to the de novo mitochondrial thymidylate biosynthesis pathway.
Gene Name
TYMS
Uniprot ID
P04818
Uniprot Name
Thymidylate synthase
Molecular Weight
35715.65 Da
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:10482907]
  2. Kubota T: [Theoretical basis for low-dose CDDP/5-FU therapy]. Gan To Kagaku Ryoho. 1999 Oct;26(11):1536-41. [PubMed:10553409]
  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:10697523]
  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:10697524]
  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:10891536]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
General Function
Transferase activity, transferring pentosyl groups
Specific Function
May have a role in maintaining the integrity of the blood vessels. Has growth promoting activity on endothelial cells, angiogenic activity in vivo and chemotactic activity on endothelial cells in v...
Gene Name
TYMP
Uniprot ID
P19971
Uniprot Name
Thymidine phosphorylase
Molecular Weight
49954.965 Da
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:14069549]
  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:18652477]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Steroid 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 oxidizes a variety of structurally un...
Gene Name
CYP2C9
Uniprot ID
P11712
Uniprot Name
Cytochrome P450 2C9
Molecular Weight
55627.365 Da
References
  1. Gunes A, Coskun U, Boruban C, Gunel N, Babaoglu MO, Sencan O, Bozkurt A, Rane A, Hassan M, Zengil H, Yasar U: Inhibitory effect of 5-fluorouracil on cytochrome P450 2C9 activity in cancer patients. Basic Clin Pharmacol Toxicol. 2006 Feb;98(2):197-200. doi: 10.1111/j.1742-7843.2006.pto_304.x. [PubMed:16445595]
  2. Brown MC: An adverse interaction between warfarin and 5-fluorouracil: A case report and review of the literature. Chemotherapy. 1999 Sep-Oct;45(5):392-5. doi: 10.1159/000007230. [PubMed:10473927]
  3. Gilbar PJ, Brodribb TR: Phenytoin and fluorouracil interaction. Ann Pharmacother. 2001 Nov;35(11):1367-70. doi: 10.1345/aph.1A051. [PubMed:11724084]
  4. Karadag O, Babaoglu MO, Altundag K, Elkiran T, Yasar U, Bozkurt A: 5-Fluorouracil-induced coronary spasm: may inhibition of hyperpolarization factors produced by CYP2C enzymes be the cause? Oncology. 2004;66(6):510-1. doi: 10.1159/000079506. [PubMed:15452381]
  5. Up to Date: Floxuridine [Link]

Drug created on June 13, 2005 07:24 / Updated on October 15, 2018 15:08