Raltitrexed
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
- 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
Reduce drug development failure ratesBuild, train, & validate machine-learning modelswith evidence-based and structured datasets.Build, train, & validate predictive machine-learning models with structured datasets.- Associated Conditions
Indication Type Indication Combined Product Details Approval Level Age Group Patient Characteristics Dose Form Treatment of Advanced colorectal cancer •••••••••••• Treatment of Pleural mesothelioma ••• ••••• - Contraindications & Blackbox Warnings
- Prevent Adverse Drug Events TodayTap into our Clinical API for life-saving information on contraindications & blackbox warnings, population restrictions, harmful risks, & more.Avoid life-threatening adverse drug events with our Clinical API
- 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.
Target Actions Organism AThymidylate synthase inhibitorHumans UFolylpolyglutamate synthase, mitochondrial antagonistHumans - 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
- Improve decision support & research outcomesWith structured adverse effects data, including: blackbox warnings, adverse reactions, warning & precautions, & incidence rates. View sample adverse effects data in our new Data Library!Improve decision support & research outcomes with our structured adverse effects data.
- 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 Browse all" title="About SNP Mediated Effects/ADRs" id="snp-actions-info" class="drug-info-popup" href="javascript:void(0);">
- Not Available
Interactions
- Drug Interactions Learn More" title="About Drug Interactions" id="structured-interactions-info" class="drug-info-popup" href="javascript:void(0);">
- 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.
Drug Interaction Integrate drug-drug
interactions in your softwareAbatacept The risk or severity of adverse effects can be increased when Raltitrexed is combined with Abatacept. Abciximab The risk or severity of bleeding can be increased when Abciximab is combined with Raltitrexed. Acenocoumarol The risk or severity of bleeding can be increased when Acenocoumarol is combined with Raltitrexed. Acetazolamide The therapeutic efficacy of Raltitrexed can be increased when used in combination with Acetazolamide. Acetylsalicylic acid The risk or severity of bleeding can be increased when Acetylsalicylic acid is combined with Raltitrexed. - Food Interactions
- No interactions found.
Products
- Drug product information from 10+ global regionsOur datasets provide approved product information including:dosage, form, labeller, route of administration, and marketing period.Access drug product information from over 10 global regions.
- Product Ingredients
Ingredient UNII CAS InChI Key Raltitrexed disodium 50VZN4BPUK Not Available HYYVJHYAMGPPLX-CKUXDGONSA-L - Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Tomudex Powder, for solution 2 mg / vial Intravenous Pfizer Canada Ulc 1996-11-18 Not applicable Canada - Unapproved/Other Products
Name Ingredients Dosage Route Labeller Marketing Start Marketing End Region Image TOMUDEX 2 MG FLAKON, 1 ADET Raltitrexed (2 mg) Injection, powder, lyophilized, for solution Intravenous ORNA İLAÇ TEKSTİL KİMYEVİ MAD. SAN. VE DIŞ TİC. LTD. ŞTİ. 2019-11-26 Not applicable Turkey
Categories
- ATC Codes
- L01BA03 — Raltitrexed
- Drug Categories
- Antimetabolites
- Antineoplastic Agents
- Antineoplastic and Immunomodulating Agents
- Enzyme Inhibitors
- Folic Acid Analogues
- Folic Acid Antagonists
- Heterocyclic Compounds, Fused-Ring
- Immunosuppressive Agents
- Myelosuppressive Agents
- Narrow Therapeutic Index Drugs
- Noxae
- Sulfur Compounds
- Thymidylate Synthase, antagonists & inhibitors
- Toxic Actions
- 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 show 8 more
- 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
- External Links
- Human Metabolome Database
- HMDB0014438
- KEGG Drug
- D01064
- KEGG Compound
- C11372
- PubChem Compound
- 104758
- PubChem Substance
- 46504880
- ChemSpider
- 94568
- BindingDB
- 50027655
- 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 / 5h3a … show 5 more
- MSDS
- Download (57 KB)
Clinical Trials
- Clinical Trials Learn More" title="About Clinical Trials" id="clinical-trials-info" class="drug-info-popup" href="javascript:void(0);">
Phase Status Purpose Conditions Count 4 Recruiting Treatment Metastatic Colorectal Cancer (CRC) 1 4 Recruiting Treatment Squamous Cell Carcinoma of the Head and Neck (SCCHN) 1 4 Unknown Status Treatment Metastatic Cancer to Liver caused by Colon Cancer 1 4 Unknown Status Treatment Metastatic Colorectal Cancer (CRC) 1 3 Completed Treatment Malignant Pleural Mesothelioma (MPM) 1
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Powder, for solution Intravenous 2 mg / vial Powder, for solution Parenteral 2 MG Injection, powder, lyophilized, for solution Intravenous 2 mg Injection, powder, for solution Parenteral - Prices
- Not Available
- Patents
- Not Available
Properties
- State
- Solid
- Experimental Properties
Property Value Source melting point (°C) 180-184 °C Not Available water solubility soluble Not Available logP -1.2 Not Available - Predicted Properties
Property Value Source Water Solubility 0.0181 mg/mL ALOGPS logP 1.65 ALOGPS logP 1.97 Chemaxon logS -4.4 ALOGPS pKa (Strongest Acidic) 3.72 Chemaxon pKa (Strongest Basic) 1.24 Chemaxon Physiological Charge -2 Chemaxon Hydrogen Acceptor Count 9 Chemaxon Hydrogen Donor Count 4 Chemaxon Polar Surface Area 148.4 Å2 Chemaxon Rotatable Bond Count 9 Chemaxon Refractivity 117.39 m3·mol-1 Chemaxon Polarizability 45.55 Å3 Chemaxon Number of Rings 3 Chemaxon Bioavailability 1 Chemaxon Rule of Five Yes Chemaxon Ghose Filter Yes Chemaxon Veber's Rule No Chemaxon MDDR-like Rule Yes Chemaxon - Predicted ADMET Features
Property Value Probability Human Intestinal Absorption - 0.6717 Blood Brain Barrier - 0.9044 Caco-2 permeable - 0.7873 P-glycoprotein substrate Substrate 0.7093 P-glycoprotein inhibitor I Non-inhibitor 0.9214 P-glycoprotein inhibitor II Non-inhibitor 0.9588 Renal organic cation transporter Non-inhibitor 0.8799 CYP450 2C9 substrate Non-substrate 0.7133 CYP450 2D6 substrate Non-substrate 0.8077 CYP450 3A4 substrate Substrate 0.6032 CYP450 1A2 substrate Non-inhibitor 0.7801 CYP450 2C9 inhibitor Non-inhibitor 0.5435 CYP450 2D6 inhibitor Non-inhibitor 0.942 CYP450 2C19 inhibitor Non-inhibitor 0.6909 CYP450 3A4 inhibitor Non-inhibitor 0.8447 CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.8351 Ames test Non AMES toxic 0.7287 Carcinogenicity Non-carcinogens 0.9442 Biodegradation Not ready biodegradable 0.9637 Rat acute toxicity 2.4511 LD50, mol/kg Not applicable hERG inhibition (predictor I) Weak inhibitor 0.9819 hERG inhibition (predictor II) Non-inhibitor 0.6763
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
- Chromatographic Properties
Collision Cross Sections (CCS)
Adduct CCS Value (Å2) Source type Source [M-H]- 213.163005 predictedDarkChem Lite v0.1.0 [M-H]- 227.503305 predictedDarkChem Lite v0.1.0 [M-H]- 197.76176 predictedDeepCCS 1.0 (2019) [M+H]+ 212.793905 predictedDarkChem Lite v0.1.0 [M+H]+ 227.286305 predictedDarkChem Lite v0.1.0 [M+H]+ 200.1573 predictedDeepCCS 1.0 (2019) [M+Na]+ 212.687005 predictedDarkChem Lite v0.1.0 [M+Na]+ 227.483905 predictedDarkChem Lite v0.1.0 [M+Na]+ 206.06984 predictedDeepCCS 1.0 (2019)
Targets
![](https://go.drugbank.com/assets/locked/DrugTargets2-682eb846d210ae4bf33ca03febccfb57bb1c61318e699b729e5df4dfab2c5b67.png)
- 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
- 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]
- 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]
- 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]
- 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]
- 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]
- Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [Article]
- 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]
- 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]
- 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
- 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 February 20, 2024 23:54