Identification

Name
Valrubicin
Accession Number
DB00385  (APRD00662)
Type
Small Molecule
Groups
Approved
Description

Valrubicin (N-trifluoroacetyladriamycin-14-valerate, Valstar®) is a chemotherapy drug used to treat bladder cancer. Valrubicin is a semisynthetic analog of the anthracycline doxorubicin, and is administered by infusion directly into the bladder. [Wikipedia]

Structure
Thumb
Synonyms
  • (8S, 10S)-8-glycoloyl-7,8,9,10-tetrahydro-6,8,11-trihydroxy-1-methoxy-10-[[2,3,6-trideoxy-3-(2,2,2-trifluoroacetamido)-α-L-lyxo-hexopyranosyl]oxy]-5,12-naphthacenedione 8²-valerate
  • 2-oxo-2-[(2S,4S)-2,5,12-trihydroxy-7-methoxy-6,11-dioxo-4-({2,3,6-trideoxy-3-[(trifluoroacetyl)amino]hexopyranosyl}oxy)-1,2,3,4,6,11-hexahydrotetracen-2-yl]ethyl pentanoate
  • Valrubicin
  • Valrubicina
  • Valrubicine
  • Valrubicinum
External IDs
AD 32 / AD-32 / NSC 246131 / NSC-246131
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
ValstarSolution, concentrate40 mg/mLIntravesicalEndo Pharmaceuticals Solutions Inc.1998-10-01Not applicableUs
ValtaxinSolution40 mgIntravesicalEndo Pharmaceuticals Solutions Inc.2001-04-23Not applicableCanada
International/Other Brands
Valstar
Categories
UNII
2C6NUM6878
CAS number
56124-62-0
Weight
Average: 723.651
Monoisotopic: 723.213874712
Chemical Formula
C34H36F3NO13
InChI Key
ZOCKGBMQLCSHFP-KQRAQHLDSA-N
InChI
InChI=1S/C34H36F3NO13/c1-4-5-9-21(40)49-13-20(39)33(47)11-16-24(19(12-33)51-22-10-17(27(41)14(2)50-22)38-32(46)34(35,36)37)31(45)26-25(29(16)43)28(42)15-7-6-8-18(48-3)23(15)30(26)44/h6-8,14,17,19,22,27,41,43,45,47H,4-5,9-13H2,1-3H3,(H,38,46)/t14-,17-,19-,22-,27+,33-/m0/s1
IUPAC Name
2-oxo-2-[(2S,4S)-2,5,12-trihydroxy-4-{[(2R,4S,5S,6S)-5-hydroxy-6-methyl-4-(2,2,2-trifluoroacetamido)oxan-2-yl]oxy}-7-methoxy-6,11-dioxo-1,2,3,4,6,11-hexahydrotetracen-2-yl]ethyl pentanoate
SMILES
[H][C@@]1(C[C@@](O)(CC2=C(O)C3=C(C(O)=C12)C(=O)C1=C(OC)C=CC=C1C3=O)C(=O)COC(=O)CCCC)O[C@H]1C[C@H](NC(=O)C(F)(F)F)[C@H](O)[C@H](C)O1

Pharmacology

Indication

For the treatment of cancer of the bladder.

Associated Conditions
Pharmacodynamics

Valrubicin is a semisynthetic analog of the anthracycline doxorubicin, and is administered by infusion directly into the bladder.

Mechanism of action

Valrubicin is an anthracycline that affects a variety of inter-related biological functions, most of which involve nucleic acid metabolism. It readily penetrates into cells, where after DNA intercalation, it inhibits the incorporation of nucleosides into nucleic acids, causes extensive chromosomal damage, and arrests cell cycle in G2. Although valrubicin does not bind strongly to DNA, a principal mechanism of its action, mediated by valrubicin metabolites, is interference with the normal DNA breaking-resealing action of DNA topoisomerase II.

TargetActionsOrganism
ADNA
intercalation
Human
ADNA topoisomerase 2-alpha
inhibitor
Human
Absorption
Not Available
Volume of distribution
Not Available
Protein binding

>99%

Metabolism

Valrubicin is metabolized to two primary metabolites: N-trifluoroacetyladriamycin and N-trifluoroacetyladriamycinol.

Route of elimination
Not Available
Half life
Not Available
Clearance
Not Available
Toxicity

The primary anticipated complications of overdosage associated with intravesical administration would be consistent with irritable bladder symptoms. Myelosuppression is possible if valrubicin is inadvertently administered systemically or if significant systemic exposure occurs following intravesical administration (e.g., in patients with bladder/rupture perforation). The maximum tolerated dose in humans by either intraperitoneal or intravenous administration is 600 mg/m2.

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteractionDrug group
AcetyldigitoxinAcetyldigitoxin may decrease the cardiotoxic activities of Valrubicin.Approved
AcetyldigoxinAcetyldigoxin may decrease the cardiotoxic activities of Valrubicin.Experimental
AncestimThe risk or severity of cytotoxicity can be increased when Ancestim is combined with Valrubicin.Approved, Investigational, Withdrawn
BevacizumabBevacizumab may increase the cardiotoxic activities of Valrubicin.Approved, Investigational
CabazitaxelThe risk or severity of adverse effects can be increased when Cabazitaxel is combined with Valrubicin.Approved
CyclophosphamideCyclophosphamide may increase the cardiotoxic activities of Valrubicin.Approved, Investigational
CymarinCymarin may decrease the cardiotoxic activities of Valrubicin.Experimental
DeslanosideDeslanoside may decrease the cardiotoxic activities of Valrubicin.Approved
DigitoxinDigitoxin may decrease the cardiotoxic activities of Valrubicin.Approved, Investigational
DigoxinDigoxin may decrease the cardiotoxic activities of Valrubicin.Approved
Digoxin Immune Fab (Ovine)Digoxin Immune Fab (Ovine) may decrease the cardiotoxic activities of Valrubicin.Approved
DocetaxelThe risk or severity of adverse effects can be increased when Docetaxel is combined with Valrubicin.Approved, Investigational
GitoformateGitoformate may decrease the cardiotoxic activities of Valrubicin.Experimental
Lanatoside CLanatoside C may decrease the cardiotoxic activities of Valrubicin.Experimental
MetildigoxinMetildigoxin may decrease the cardiotoxic activities of Valrubicin.Experimental
OleandrinOleandrin may decrease the cardiotoxic activities of Valrubicin.Experimental, Investigational
OuabainOuabain may decrease the cardiotoxic activities of Valrubicin.Approved
PaclitaxelThe risk or severity of adverse effects can be increased when Paclitaxel is combined with Valrubicin.Approved, Vet Approved
PeruvosidePeruvoside may decrease the cardiotoxic activities of Valrubicin.Experimental
ProscillaridinProscillaridin may decrease the cardiotoxic activities of Valrubicin.Experimental
TrastuzumabTrastuzumab may increase the cardiotoxic activities of Valrubicin.Approved, Investigational
Food Interactions
Not Available

References

Synthesis Reference

Francesca Scarpitta, Csilla Nemethne Racz, "Crystalline forms of valrubicin and processes for their preparation." U.S. Patent US20080139490, issued June 12, 2008.

US20080139490
General References
Not Available
External Links
PubChem Compound
454216
PubChem Substance
46506642
ChemSpider
399974
ChEBI
135876
ChEMBL
CHEMBL1096885
Therapeutic Targets Database
DAP000650
PharmGKB
PA164748616
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Valrubicin
ATC Codes
L01DB09 — Valrubicin
FDA label
Download (80 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedTreatmentTransitional Cell Carcinoma1
2CompletedTreatmentBladder Cancers2
2, 3CompletedTreatmentBladder Cancers / Carcinoma in Situ1
3TerminatedTreatmentCarcinoma in Situ / Non-muscle Invasive Bladder Cancer (NMIBC) / Transitional Cell Carcinoma1
3Unknown StatusTreatmentBladder Cancers1

Pharmacoeconomics

Manufacturers
  • Endo pharmaceutical solutions inc
Packagers
  • Endo Pharmaceuticals Inc.
  • Primapharm Inc.
Dosage forms
FormRouteStrength
Solution, concentrateIntravesical40 mg/mL
SolutionIntravesical40 mg
Prices
Unit descriptionCostUnit
Valstar 40 mg/ml vial219.96USD ml
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)116-117 °CNot Available
water solubilityinsolubleNot Available
logP2.2Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.0325 mg/mLALOGPS
logP2.67ALOGPS
logP4.49ChemAxon
logS-4.4ALOGPS
pKa (Strongest Acidic)8ChemAxon
pKa (Strongest Basic)-3.4ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count12ChemAxon
Hydrogen Donor Count5ChemAxon
Polar Surface Area215.22 Å2ChemAxon
Rotatable Bond Count12ChemAxon
Refractivity168.03 m3·mol-1ChemAxon
Polarizability69.2 Å3ChemAxon
Number of Rings5ChemAxon
Bioavailability0ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.8596
Blood Brain Barrier-0.8907
Caco-2 permeable-0.6894
P-glycoprotein substrateSubstrate0.8165
P-glycoprotein inhibitor INon-inhibitor0.5747
P-glycoprotein inhibitor IINon-inhibitor0.5584
Renal organic cation transporterNon-inhibitor0.9348
CYP450 2C9 substrateNon-substrate0.8061
CYP450 2D6 substrateNon-substrate0.7947
CYP450 3A4 substrateSubstrate0.7203
CYP450 1A2 substrateNon-inhibitor0.7239
CYP450 2C9 inhibitorNon-inhibitor0.8228
CYP450 2D6 inhibitorNon-inhibitor0.9016
CYP450 2C19 inhibitorNon-inhibitor0.7565
CYP450 3A4 inhibitorNon-inhibitor0.6895
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.7154
Ames testNon AMES toxic0.5421
CarcinogenicityNon-carcinogens0.9272
BiodegradationNot ready biodegradable0.9972
Rat acute toxicity2.8652 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9846
hERG inhibition (predictor II)Inhibitor0.5129
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
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 anthracyclines. These are polyketides containing a tetracenequinone ring structure with a sugar attached by glycosidic linkage.
Kingdom
Organic compounds
Super Class
Phenylpropanoids and polyketides
Class
Anthracyclines
Sub Class
Not Available
Direct Parent
Anthracyclines
Alternative Parents
Tetracenequinones / Anthraquinones / O-glycosyl compounds / Tetralins / Anisoles / Aryl ketones / Alkyl aryl ethers / Alpha-acyloxy ketones / Fatty acid esters / Oxanes
show 17 more
Substituents
Anthracycline / Anthracyclinone-skeleton / Tetracenequinone / 9,10-anthraquinone / 1,4-anthraquinone / Anthracene / Glycosyl compound / O-glycosyl compound / Tetralin / Aryl ketone
show 37 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
Not Available

Targets

1. DNA
Kind
Nucleotide
Organism
Human
Pharmacological action
Yes
Actions
Intercalation
General Function:
Used for biological information storage.
Specific Function:
DNA contains the instructions needed for an organism to develop, survive and reproduce.
Molecular Weight:
2.15 x 1012 Da
References
  1. Brox L, Gowans B, Belch A: N-trifluoroacetyladriamycin-14-valerate and adriamycin induced DNA damage in the RPMI-6410 human lymphoblastoid cell line. Can J Biochem. 1980 Sep;58(9):720-5. [PubMed:7006761]
  2. Perabo FG, Muller SC: New agents in intravesical chemotherapy of superficial bladder cancer. Scand J Urol Nephrol. 2005;39(2):108-16. [PubMed:16019763]
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Inhibitor
General Function
Ubiquitin binding
Specific Function
Control of topological states of DNA by transient breakage and subsequent rejoining of DNA strands. Topoisomerase II makes double-strand breaks. Essential during mitosis and meiosis for proper segr...
Gene Name
TOP2A
Uniprot ID
P11388
Uniprot Name
DNA topoisomerase 2-alpha
Molecular Weight
174383.88 Da
References
  1. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352]
  2. Perabo FG, Muller SC: New agents in intravesical chemotherapy of superficial bladder cancer. Scand J Urol Nephrol. 2005;39(2):108-16. [PubMed:16019763]

Drug created on June 13, 2005 07:24 / Updated on July 02, 2018 17:17