Identification

Summary

Raltitrexed is a folate analog thymidylate synthase inhibitor used in the treatment of advanced colorectal cancer.

Brand Names
Tomudex
Generic Name
Raltitrexed
DrugBank Accession Number
DB00293
Background

Raltitrexed (brand name Tomudex®) is a chemotherapy drug manufactured AstraZeneca Company, is an antimetabolite used in chemotherapy. It is an inhibitor of thymidylate synthase.

Type
Small Molecule
Groups
Approved, Investigational
Structure
Thumb
Weight
Average: 458.488
Monoisotopic: 458.126005146
Chemical Formula
C21H22N4O6S
Synonyms
  • Raltitrexed
External IDs
  • ZD 1694
  • ZD-1694
  • ZD1694

Pharmacology

Indication

For the treatment of malignant neoplasm of colon and rectum

Pharmacology
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Associated Conditions
Contraindications & Blackbox Warnings
Contraindications
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Pharmacodynamics

Raltitrexed belongs to a group of medicines known as antimetabolites. It is used to treat cancer of the colon and rectum. It may also be used to treat other kinds of cancer, as determined by your doctor. Raltitrexed blocks an enzyme needed by the cell to live. This interferes with the growth of cancer cells, which are eventually destroyed. Since the growth of normal body cells may also be affected by raltitrexed, other effects will also occur. Some of these may be serious and must be reported to your doctor. Other effects, like hair loss, may not be serious but may cause concern.

Mechanism of action

Raltitrexed is an antineoplastic Agents and folic acid antagonists. Raltitrexed inhibits thymidylate synthase (TS) leading to DNA fragmentation and cell death. It is transported into cells via a reduced folate carrier. Inside the cell Raltitrexed is extensively polyglutamated, which enhances thymidylate synthase inhibitory power and duration. Inhibition of this enzyme results in decreased synthesis of thymidine triphosphate which is required for DNA synthesis.

TargetActionsOrganism
AThymidylate synthase
inhibitor
Humans
UFolylpolyglutamate synthase, mitochondrial
antagonist
Humans
Absorption

Not Available

Volume of distribution

Not Available

Protein binding

>93%

Metabolism

Raltitrexed is transported into cells via a reduced folate carrier. Inside the cell it is extensively polyglutamated by the enzyme folyl polyglutamate synthetase to polyglutamate forms.

Route of elimination

Not Available

Half-life

198 hours

Clearance

Not Available

Adverse Effects
Adverseeffects
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Toxicity

Side effects include pale skin, troubled breathing, unusual bleeding or bruising, unusual tiredness or weakness, black, tarry stools, chest pain, chills, cough, fever, painful or difficult urination, shortness of breath, sore throat, sores, ulcers, or white spots on lips or in mouth, swollen glands, increase in bowel movements, loose stools, soft stools.

Pathways
Not Available
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
AbataceptThe risk or severity of adverse effects can be increased when Raltitrexed is combined with Abatacept.
AbciximabThe risk or severity of bleeding can be increased when Abciximab is combined with Raltitrexed.
AcenocoumarolThe risk or severity of bleeding can be increased when Acenocoumarol is combined with Raltitrexed.
AcetazolamideThe therapeutic efficacy of Raltitrexed can be increased when used in combination with Acetazolamide.
Acetylsalicylic acidThe risk or severity of bleeding can be increased when Acetylsalicylic acid is combined with Raltitrexed.
AdalimumabThe risk or severity of adverse effects can be increased when Adalimumab is combined with Raltitrexed.
Adenovirus type 7 vaccine liveThe risk or severity of infection can be increased when Adenovirus type 7 vaccine live is combined with Raltitrexed.
AldesleukinThe risk or severity of adverse effects can be increased when Aldesleukin is combined with Raltitrexed.
AlefaceptThe risk or severity of adverse effects can be increased when Alefacept is combined with Raltitrexed.
AlemtuzumabThe risk or severity of adverse effects can be increased when Alemtuzumab is combined with Raltitrexed.
Interactions
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Food Interactions
No interactions found.

Products

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Product Ingredients
IngredientUNIICASInChI Key
Raltitrexed disodium50VZN4BPUKNot AvailableHYYVJHYAMGPPLX-CKUXDGONSA-L
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
TomudexPowder, for solution2 mg / vialIntravenousPfizer Canada Ulc1996-11-18Not applicableCanada flag
Unapproved/Other Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing EndRegionImage
TOMUDEX 2 MG FLAKON, 1 ADETRaltitrexed (2 mg)Injection, powder, lyophilized, for solutionIntravenousORNA İLAÇ TEKSTİL KİMYEVİ MAD. SAN. VE DIŞ TİC. LTD. ŞTİ.2020-08-14Not applicableTurkey flag

Categories

ATC Codes
L01BA03 — Raltitrexed
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as glutamic acid and derivatives. These are compounds containing glutamic acid or a derivative thereof resulting from reaction of glutamic acid at the amino group or the carboxy group, or from the replacement of any hydrogen of glycine by a heteroatom.
Kingdom
Organic compounds
Super Class
Organic acids and derivatives
Class
Carboxylic acids and derivatives
Sub Class
Amino acids, peptides, and analogues
Direct Parent
Glutamic acid and derivatives
Alternative Parents
N-acyl-alpha amino acids / Quinazolines / Thiophene carboxamides / 2-heteroaryl carboxamides / Dialkylarylamines / 2,5-disubstituted thiophenes / Hydroxypyrimidines / 2-aminothiophenes / Benzenoids / Dicarboxylic acids and derivatives
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Substituents
2,5-disubstituted thiophene / 2-aminothiophene / 2-heteroaryl carboxamide / Aromatic heteropolycyclic compound / Azacycle / Benzenoid / Carbonyl group / Carboxamide group / Carboxylic acid / Dialkylarylamine
show 21 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
N-acyl-amino acid (CHEBI:5847)
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
FCB9EGG971
CAS number
112887-68-0
InChI Key
IVTVGDXNLFLDRM-HNNXBMFYSA-N
InChI
InChI=1S/C21H22N4O6S/c1-11-22-14-4-3-12(9-13(14)19(28)23-11)10-25(2)17-7-6-16(32-17)20(29)24-15(21(30)31)5-8-18(26)27/h3-4,6-7,9,15H,5,8,10H2,1-2H3,(H,24,29)(H,26,27)(H,30,31)(H,22,23,28)/t15-/m0/s1
IUPAC Name
(2S)-2-[(5-{methyl[(2-methyl-4-oxo-1,4-dihydroquinazolin-6-yl)methyl]amino}thiophen-2-yl)formamido]pentanedioic acid
SMILES
CN(CC1=CC2=C(NC(C)=NC2=O)C=C1)C1=CC=C(S1)C(=O)N[C@@H](CCC(O)=O)C(O)=O

References

Synthesis Reference
US4992550
General References
Not Available
Human Metabolome Database
HMDB0014438
KEGG Drug
D01064
KEGG Compound
C11372
PubChem Compound
104758
PubChem Substance
46504880
ChemSpider
94568
BindingDB
18795
RxNav
196239
ChEBI
5847
ChEMBL
CHEMBL225071
ZINC
ZINC000003832372
Therapeutic Targets Database
DAP000759
PharmGKB
PA131625240
PDBe Ligand
D16
Wikipedia
Raltitrexed
PDB Entries
1hvy / 1i00 / 1rts / 2kce / 2tsr / 3nrr / 4eb4 / 4fox / 4gtb / 4iqq
show 5 more
MSDS
Download (57 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4RecruitingTreatmentSquamous Cell Carcinoma Head and Neck Cancer (HNSCC)1
4Unknown StatusTreatmentLiver Metastasis Colon Cancer1
4Unknown StatusTreatmentMetastatic Colorectal Cancer (CRC)1
3CompletedTreatmentMalignant Pleural Mesothelioma (MPM)1
3TerminatedTreatmentColorectal Cancer / Liver Metastasis1
3Unknown StatusTreatmentColorectal Cancer1
3Unknown StatusTreatmentHead and Neck Cancers- Squamous Cell1
2Active Not RecruitingTreatmentEsophagus Squamous Cell Carcinoma (SCC)1
2Active Not RecruitingTreatmentRecurrent Colorectal Cancer1
2CompletedTreatmentAdenocarcinoma of Colon / Adenocarcinoma of Rectum / Metastatic Disease1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Powder, for solutionIntravenous2 mg / vial
Powder, for solutionParenteral2 MG
Injection, powder, lyophilized, for solutionIntravenous2 mg
Injection, powder, lyophilized, for solutionIntravenous
Injection, powder, for solutionParenteral
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)180-184 °CNot Available
water solubilitysolubleNot Available
logP-1.2Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.0181 mg/mLALOGPS
logP1.65ALOGPS
logP1.97ChemAxon
logS-4.4ALOGPS
pKa (Strongest Acidic)3.72ChemAxon
pKa (Strongest Basic)-0.46ChemAxon
Physiological Charge-2ChemAxon
Hydrogen Acceptor Count9ChemAxon
Hydrogen Donor Count4ChemAxon
Polar Surface Area148.4 Å2ChemAxon
Rotatable Bond Count9ChemAxon
Refractivity117.39 m3·mol-1ChemAxon
Polarizability45.55 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
Predicted ADMET Features
PropertyValueProbability
Human Intestinal Absorption-0.6717
Blood Brain Barrier-0.9044
Caco-2 permeable-0.7873
P-glycoprotein substrateSubstrate0.7093
P-glycoprotein inhibitor INon-inhibitor0.9214
P-glycoprotein inhibitor IINon-inhibitor0.9588
Renal organic cation transporterNon-inhibitor0.8799
CYP450 2C9 substrateNon-substrate0.7133
CYP450 2D6 substrateNon-substrate0.8077
CYP450 3A4 substrateSubstrate0.6032
CYP450 1A2 substrateNon-inhibitor0.7801
CYP450 2C9 inhibitorNon-inhibitor0.5435
CYP450 2D6 inhibitorNon-inhibitor0.942
CYP450 2C19 inhibitorNon-inhibitor0.6909
CYP450 3A4 inhibitorNon-inhibitor0.8447
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.8351
Ames testNon AMES toxic0.7287
CarcinogenicityNon-carcinogens0.9442
BiodegradationNot ready biodegradable0.9637
Rat acute toxicity2.4511 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9819
hERG inhibition (predictor II)Non-inhibitor0.6763
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 GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
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
MS/MS Spectrum - , positiveLC-MS/MSsplash10-03k9-0709000000-b0a922c0009fee349863

Targets

Drugtargets2
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Details
1. Thymidylate synthase
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
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. Yin MB, Guo B, Panadero A, Frank C, Wrzosek C, Slocum HK, Rustum YM: Cyclin E-cdk2 activation is associated with cell cycle arrest and inhibition of DNA replication induced by the thymidylate synthase inhibitor Tomudex. Exp Cell Res. 1999 Feb 25;247(1):189-99. [Article]
  2. Cao S, McGuire JJ, Rustum YM: Antitumor activity of ZD1694 (tomudex) against human head and neck cancer in nude mouse models: role of dosing schedule and plasma thymidine. Clin Cancer Res. 1999 Jul;5(7):1925-34. [Article]
  3. 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. [Article]
  4. Orlandi L, Bearzatto A, Abolafio G, De Marco C, Daidone MG, Zaffaroni N: Involvement of bcl-2 and p21waf1 proteins in response of human breast cancer cell clones to Tomudex. Br J Cancer. 1999 Sep;81(2):252-60. [Article]
  5. Grem JL, Sorensen JM, Cullen E, Takimoto CH, Steinberg SM, Chen AP, Hamilton JM, Arbuck SG, McAtee N, Lawrence D, Goldspiel B, Johnston PG, Allegra CJ: A Phase I study of raltitrexed, an antifolate thymidylate synthase inhibitor, in adult patients with advanced solid tumors. Clin Cancer Res. 1999 Sep;5(9):2381-91. [Article]
  6. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [Article]
  7. Yang Z, Waldman AS, Wyatt MD: DNA damage and homologous recombination signaling induced by thymidylate deprivation. Biochem Pharmacol. 2008 Oct 15;76(8):987-96. doi: 10.1016/j.bcp.2008.08.010. Epub 2008 Aug 19. [Article]
  8. Chen VJ, Bewley JR, Andis SL, Schultz RM, Iversen PW, Shih C, Mendelsohn LG, Seitz DE, Tonkinson JL: Cellular pharmacology of MTA: a correlation of MTA-induced cellular toxicity and in vitro enzyme inhibition with its effect on intracellular folate and nucleoside triphosphate pools in CCRF-CEM cells. Semin Oncol. 1999 Apr;26(2 Suppl 6):48-54. [Article]
  9. Berman HM, Westbrook J, Feng Z, Gilliland G, Bhat TN, Weissig H, Shindyalov IN, Bourne PE: The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Antagonist
General Function
Tetrahydrofolylpolyglutamate synthase activity
Specific Function
Catalyzes conversion of folates to polyglutamate derivatives allowing concentration of folate compounds in the cell and the intracellular retention of these cofactors, which are important substrate...
Gene Name
FPGS
Uniprot ID
Q05932
Uniprot Name
Folylpolyglutamate synthase, mitochondrial
Molecular Weight
64608.53 Da
References
  1. Innocenti F, Ratain MJ: Update on pharmacogenetics in cancer chemotherapy. Eur J Cancer. 2002 Mar;38(5):639-44. [Article]

Drug created at June 13, 2005 13:24 / Updated at January 19, 2022 01:13