Vindesine

Identification

Summary

Vindesine is a vinca alkaloid derived from vinblastine used for various types of malignancies, but mainly acute lymphocytic leukemia (ALL).

Generic Name
Vindesine
DrugBank Accession Number
DB00309
Background

Vinblastine derivative with antineoplastic activity against cancer. Major side effects are myelosuppression and neurotoxicity. Vindesine is used extensively in chemotherapy protocols (antineoplastic combined chemotherapy protocols).

Type
Small Molecule
Groups
Approved, Investigational
Structure
Weight
Average: 753.941
Monoisotopic: 753.410149131
Chemical Formula
C43H55N5O7
Synonyms
  • 3-(aminocarbonyl)-O4-deacetyl-3-de(methoxycarbonyl)vincaleukoblastine
  • 3-carbamoyl-4-deacetyl-3-de(methoxycarbonyl)vincaleukoblastine
  • Desacetylvinblastine amide
  • Vindesina
  • Vindesine
  • Vindesinum
External IDs
  • Lilly 112531

Pharmacology

Indication

For the treatment of acute leukaemia, malignant lymphoma, Hodgkin's disease, acute erythraemia and acute panmyelosis

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Associated Conditions
Indication TypeIndicationCombined Product DetailsApproval LevelAge GroupPatient CharacteristicsDose Form
Treatment ofAcute lymphocytic leukemia (all)•••••••••••••••••••••••••••••• •• •••••••••••• ••••••••••••••••• ••••••• ••• ••••••••
Treatment ofBlast crisis•••••••••••••••••••••• ••••••• ••• ••••••••
Treatment ofMelanoma, malignant••••••••••••••••••••• •• •••••••••••• ••••••••••••••••• ••••••• ••• ••••••••
Contraindications & Blackbox Warnings
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Pharmacodynamics

Vindesine is indicated for the treatment of acute lymphocytic leukemia of childhood that is resistant to vincristine and non-oat cell lung cancer. Vindesine causes the arrest of cells in metaphase mitosis. It is three times more potent than vincristine and nearly 10 times more potent than vinblastine in causing mitotic arrest in in vitro studies at doses designed to arrest from 10 to 15% of the cells in mitosis. Vindesine and vincristine are approximately equipotent at dose levels that arrest 40 to 50% of the cells in mitosis. Unlike vinblastine, vindesine produces very few postmetaphase cells. Vindesine has demonstrated activity in patients who have relapsed while receiving multiple-agent treatment that included vincristine.

Mechanism of action

Vindesine acts by causing the arrest of cells in metaphase mitosis through its inhibition tubulin mitotic funcitoning. The drug is cell-cycle specific for the S phase.

TargetActionsOrganism
ATubulin beta-1 chain
inhibitor
Humans
Absorption

Not Available

Volume of distribution

Not Available

Protein binding

65-75%

Metabolism

Hepatic

Route of elimination

Not Available

Half-life

24 hours.

Clearance

Not Available

Adverse Effects
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Toxicity

Not Available

Pathways
PathwayCategory
Vindesine Action PathwayDrug action
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
AbametapirThe serum concentration of Vindesine can be increased when it is combined with Abametapir.
AbataceptThe metabolism of Vindesine can be increased when combined with Abatacept.
AbciximabThe risk or severity of bleeding can be increased when Abciximab is combined with Vindesine.
AcalabrutinibThe metabolism of Vindesine can be decreased when combined with Acalabrutinib.
AcenocoumarolThe risk or severity of bleeding can be increased when Acenocoumarol is combined with Vindesine.
Food Interactions
  • Exercise caution with grapefruit products. Vindesine is metabolized by CYP3A4, and grapefruit inhibits CYP3A4 metabolism, which may increase vindesine serum levels.
  • Exercise caution with St. John's Wort. Vindesine is metabolized by CYP3A4 and this herb induces CYP3A4 metabolism, which may reduce vindesine serum levels.

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Product Ingredients
IngredientUNIICASInChI Key
Vindesine sulfateCPH2U7DNDY59917-39-4COFJBSXICYYSKG-OAUVCNBTSA-N
International/Other Brands
Eldesine / Eldisine
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
Eldisine Inj 5mg/2mlPowder, for solution5 mg / vialIntravenousEli Lilly & Co. Ltd.1982-12-312000-08-03Canada flag

Categories

ATC Codes
L01CA03 — Vindesine
Drug Categories
Classification
Not classified
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
RSA8KO39WH
CAS number
53643-48-4
InChI Key
HHJUWIANJFBDHT-ZVTSDNJWSA-N
InChI
InChI=1S/C43H55N5O7/c1-6-39(52)21-25-22-42(38(51)55-5,33-27(13-17-47(23-25)24-39)26-11-8-9-12-30(26)45-33)29-19-28-31(20-32(29)54-4)46(3)35-41(28)15-18-48-16-10-14-40(7-2,34(41)48)36(49)43(35,53)37(44)50/h8-12,14,19-20,25,34-36,45,49,52-53H,6-7,13,15-18,21-24H2,1-5H3,(H2,44,50)/t25-,34-,35+,36+,39-,40+,41+,42-,43-/m0/s1
IUPAC Name
methyl (13S,15R,17S)-13-[(1R,9R,10S,11R,12R,19R)-10-carbamoyl-12-ethyl-10,11-dihydroxy-5-methoxy-8-methyl-8,16-diazapentacyclo[10.6.1.0^{1,9}.0^{2,7}.0^{16,19}]nonadeca-2,4,6,13-tetraen-4-yl]-17-ethyl-17-hydroxy-1,11-diazatetracyclo[13.3.1.0^{4,12}.0^{5,10}]nonadeca-4(12),5(10),6,8-tetraene-13-carboxylate
SMILES
[H][C@@]12N3CC[C@@]11C4=CC(=C(OC)C=C4N(C)[C@@]1([H])[C@](O)([C@H](O)[C@]2(CC)C=CC3)C(N)=O)[C@]1(C[C@@]2([H])CN(C[C@](O)(CC)C2)CCC2=C1NC1=C2C=CC=C1)C(=O)OC

References

Synthesis Reference

Stanislaw Rolski, "Method of preparing vindesine sulfate." U.S. Patent US4259242, issued September, 1965.

US4259242
General References
Not Available
Human Metabolome Database
HMDB0014454
KEGG Drug
D01769
PubChem Compound
40839
PubChem Substance
46504548
ChemSpider
9818189
RxNav
11204
ChEBI
36373
ChEMBL
CHEMBL238071
ZINC
ZINC000008214470
Therapeutic Targets Database
DAP000949
PharmGKB
PA10232
RxList
RxList Drug Page
Wikipedia
Vindesine

Clinical Trials

Clinical Trials

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Injection, powder, for solutionParenteral5 mg
Injection, powder, for solutionIntravenous; Parenteral5 MG
Powder, for solutionIntravenous5 mg
Powder, for solutionIntravenous5 mg / vial
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)230-232 °CNot Available
logP2.9Not Available
Predicted Properties
PropertyValueSource
logP2.79Chemaxon
pKa (Strongest Acidic)11.34Chemaxon
pKa (Strongest Basic)9.09Chemaxon
Physiological Charge2Chemaxon
Hydrogen Acceptor Count9Chemaxon
Hydrogen Donor Count5Chemaxon
Polar Surface Area164.82 Å2Chemaxon
Rotatable Bond Count7Chemaxon
Refractivity210.32 m3·mol-1Chemaxon
Polarizability81.39 Å3Chemaxon
Number of Rings9Chemaxon
Bioavailability1Chemaxon
Rule of FiveNoChemaxon
Ghose FilterNoChemaxon
Veber's RuleNoChemaxon
MDDR-like RuleYesChemaxon
Predicted ADMET Features
PropertyValueProbability
Human Intestinal Absorption+0.9027
Blood Brain Barrier-0.9821
Caco-2 permeable-0.5154
P-glycoprotein substrateSubstrate0.9164
P-glycoprotein inhibitor INon-inhibitor0.5717
P-glycoprotein inhibitor IINon-inhibitor0.6577
Renal organic cation transporterNon-inhibitor0.8851
CYP450 2C9 substrateNon-substrate0.8468
CYP450 2D6 substrateNon-substrate0.9116
CYP450 3A4 substrateSubstrate0.7597
CYP450 1A2 substrateNon-inhibitor0.8766
CYP450 2C9 inhibitorNon-inhibitor0.8798
CYP450 2D6 inhibitorNon-inhibitor0.8911
CYP450 2C19 inhibitorNon-inhibitor0.8814
CYP450 3A4 inhibitorNon-inhibitor0.811
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.933
Ames testNon AMES toxic0.8682
CarcinogenicityNon-carcinogens0.8976
BiodegradationNot ready biodegradable1.0
Rat acute toxicity2.9430 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9892
hERG inhibition (predictor II)Inhibitor0.6584
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/MSsplash10-0udr-0000001900-33ad5881d5ff5244fc25
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSsplash10-004l-0000009200-18acd4d40a0145f034ea
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSsplash10-0gdr-0000004900-79300836d165db395653
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSsplash10-004m-0000009100-42f72e0ac830101408fe
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSsplash10-0f8i-0221109300-344c45139766ca438416
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSsplash10-022c-0020009000-9b612b580e76fd9b6262
Chromatographic Properties
Collision Cross Sections (CCS)
Not Available

Targets

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Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
General Function
Structural constituent of cytoskeleton
Specific Function
Tubulin is the major constituent of microtubules. It binds two moles of GTP, one at an exchangeable site on the beta chain and one at a non-exchangeable site on the alpha chain (By similarity).
Gene Name
TUBB1
Uniprot ID
Q9H4B7
Uniprot Name
Tubulin beta-1 chain
Molecular Weight
50326.56 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. [Article]
  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. [Article]
  3. Natsume T, Watanabe J, Tamaoki S, Fujio N, Miyasaka K, Kobayashi M: Characterization of the interaction of TZT-1027, a potent antitumor agent, with tubulin. Jpn J Cancer Res. 2000 Jul;91(7):737-47. [Article]
  4. Yoshida M, Matsui Y, Ikarashi Y, Usui T, Osada H, Wakasugi H: Antiproliferating activity of the mitotic inhibitor pironetin against vindesine- and paclitaxel-resistant human small cell lung cancer H69 cells. Anticancer Res. 2007 Mar-Apr;27(2):729-36. [Article]
  5. Fiebig HH, Schuler J, Bausch N, Hofmann M, Metz T, Korrat A: Gene signatures developed from patient tumor explants grown in nude mice to predict tumor response to 11 cytotoxic drugs. Cancer Genomics Proteomics. 2007 May-Jun;4(3):197-209. [Article]

Enzymes

Kind
Protein
Organism
Humans
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 react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
References
  1. Ekins S, Bravi G, Wikel JH, Wrighton SA: Three-dimensional-quantitative structure activity relationship analysis of cytochrome P-450 3A4 substrates. J Pharmacol Exp Ther. 1999 Oct;291(1):424-33. [Article]
  2. Smith NF, Mani S, Schuetz EG, Yasuda K, Sissung TM, Bates SE, Figg WD, Sparreboom A: Induction of CYP3A4 by vinblastine: Role of the nuclear receptor NR1I2. Ann Pharmacother. 2010 Nov;44(11):1709-17. doi: 10.1345/aph.1P354. Epub 2010 Oct 19. [Article]
  3. Zhou XJ, Zhou-Pan XR, Gauthier T, Placidi M, Maurel P, Rahmani R: Human liver microsomal cytochrome P450 3A isozymes mediated vindesine biotransformation. Metabolic drug interactions. Biochem Pharmacol. 1993 Feb 24;45(4):853-61. [Article]

Drug created at June 13, 2005 13:24 / Updated at March 03, 2024 02:31