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

Structure

Similar Structures

Synonyms

Raltitrexed

External IDs

ZD 1694 / ZD-1694 / ZD1694

Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End
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Tomudex	Powder, for solution	2 mg	Intravenous	Pfizer	1996-11-18	Not applicable

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Application Number

A unique ID assigned by the FDA when a product is submitted for approval by the labeller.

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Product Code

A governmentally-recognized ID which uniquely identifies the product within its regulatory market.

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Categories

UNII

FCB9EGG971

CAS number

112887-68-0

Weight

Average: 458.488
Monoisotopic: 458.126005146

Chemical Formula

C₂₁H₂₂N₄O₆S

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

Pharmacology

Indication

For the treatment of malignant neoplasm of colon and rectum

Associated Conditions

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	inhibitor	Humans
UFolylpolyglutamate synthase, mitochondrial	antagonist	Humans

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Adverse Effects

Comprehensive structured data on known drug adverse effects with statistical prevalence. MedDRA and ICD10 ids are provided for adverse effect conditions and symptoms.

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Contraindications

Structured data covering drug contraindications. Each contraindication describes a scenario in which the drug is not to be used. Includes restrictions on co-administration, contraindicated populations, and more.

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Blackbox Warnings

Structured data representing warnings from the black box section of drug labels. These warnings cover important and dangerous risks, contraindications, or adverse effects.

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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

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.

Affected organisms

Humans and other mammals

Pathways

Not Available

Pharmacogenomic Effects/ADRs

Not Available

Interactions

Drug Interactions

Drug	Interaction
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(6R)-Folinic acid	The therapeutic efficacy of Raltitrexed can be decreased when used in combination with (6R)-Folinic acid.
(6S)-5,6,7,8-tetrahydrofolate	The therapeutic efficacy of Raltitrexed can be decreased when used in combination with (6S)-5,6,7,8-tetrahydrofolate.
(R)-warfarin	The risk or severity of bleeding can be increased when (R)-warfarin is combined with Raltitrexed.
(S)-Warfarin	The risk or severity of bleeding can be increased when (S)-Warfarin is combined with Raltitrexed.
2-Methoxyethanol	The risk or severity of adverse effects can be increased when Raltitrexed is combined with 2-Methoxyethanol.
4-hydroxycoumarin	The risk or severity of bleeding can be increased when 4-hydroxycoumarin is combined with Raltitrexed.
5-methyltetrahydrofolic acid	The therapeutic efficacy of Raltitrexed can be decreased when used in combination with 5-methyltetrahydrofolic acid.
9-(N-methyl-L-isoleucine)-cyclosporin A	The risk or severity of adverse effects can be increased when Raltitrexed is combined with 9-(N-methyl-L-isoleucine)-cyclosporin A.
Abatacept	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.

Additional Data Available

Extended Description

Extended description of the mechanism of action and particular properties of each drug interaction.

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Severity

A severity rating for each drug interaction, from minor to major.

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Evidence Level

A rating for the strength of the evidence supporting each drug interaction.

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Action

Evidence Level

An effect category for each drug interaction. Know how this interaction affects the subject drug.

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Food Interactions

Not Available

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: 18795
ChEBI: 5847
ChEMBL: CHEMBL225071
Therapeutic Targets Database: DAP000759
PharmGKB: PA131625240
HET: D16
Wikipedia: Raltitrexed

ATC Codes

L01BA03 — Raltitrexed

PDB Entries

1hvy / 1i00 / 1rts / 2kce / 2tsr / 3nrr / 4eb4 / 4fox / 4gtb / 4iqq …

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MSDS

Download (57 KB)

Clinical Trials

Clinical Trials

Phase	Status	Purpose	Conditions	Count
1	Completed	Treatment	Colorectal Cancers	1
1	Completed	Treatment	Neoplasms	1
1	Completed	Treatment	Recurrent Childhood Acute Lymphoblastic Leukemia / Recurrent Childhood Acute Myeloid Leukemia	1
1	Completed	Treatment	Unspecified Adult Solid Tumor, Protocol Specific	2
2	Active Not Recruiting	Treatment	Rectal Carcinoma	1
2	Completed	Treatment	Adenocarcinoma of Colon / Adenocarcinoma of Rectum / Metastatic Disease	1
2	Completed	Treatment	Colorectal Cancers / Hepatic Metastases	1
2	Completed	Treatment	Inoperable or Recurrent Rectal Cancer	1
2	Completed	Treatment	Mesothelioma, Malignant	1
2	Completed	Treatment	Rectal Neoplasms	1
2	Not Yet Recruiting	Treatment	Colorectal Cancers	1
2	Not Yet Recruiting	Treatment	Recurrent Colorectal Carcinoma / Thrombocytopenias	1
2	Recruiting	Treatment	Adenocarcinomas of the Gastroesophageal Junction / Malignant Neoplasm of Stomach	1
2	Recruiting	Treatment	Advanced Colorectal Cancer	1
2	Recruiting	Treatment	Colorectal Cancers	1
2	Recruiting	Treatment	Esophagus Squamous Cell Carcinoma	1
2	Recruiting	Treatment	Malignant Neoplasm of Stomach	1
2	Recruiting	Treatment	Metastatic Colon Cancer	1
2	Recruiting	Treatment	Nasopharyngeal Carcinoma	1
2	Recruiting	Treatment	Rectal Neoplasms Malignant	1
2	Unknown Status	Treatment	Carcinoma, Colorectal	1
2	Unknown Status	Treatment	Inoperable Esophageal Cancer Stage I-III	1
2, 3	Completed	Treatment	Colorectal Cancers	1
3	Completed	Treatment	Mesothelioma, Malignant	1
3	Recruiting	Treatment	Head and Neck Squamous Cell Cancer	1
3	Unknown Status	Treatment	Colorectal Cancers	1
4	Recruiting	Treatment	Colon Cancer Liver Metastasis	1
4	Recruiting	Treatment	Head and Neck Squamous Cell Carcinoma (HNSCC)	1
4	Recruiting	Treatment	Metastatic Colorectal Cancers	1

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Not Available

Dosage forms

Form	Route	Strength
Powder, for solution	Intravenous	2 mg

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)	-0.46	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

ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)

Not Available

Spectra

Spectrum	Spectrum Type	Splash Key
Predicted GC-MS Spectrum - GC-MS	Predicted GC-MS	Not Available
Predicted MS/MS Spectrum - 10V, Positive (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)	Predicted LC-MS/MS	Not Available
MS/MS Spectrum - , positive	LC-MS/MS	splash10-03k9-0709000000-b0a922c0009fee349863

Taxonomy

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: Glutamic acid or derivatives / N-acyl-alpha-amino acid / N-acyl-alpha amino acid or derivatives / Diazanaphthalene / Quinazoline / 2-heteroaryl carboxamide / Thiophene carboxamide / Thiophene carboxylic acid or derivatives / Dialkylarylamine / Hydroxypyrimidine
show 21 more
Molecular Framework: Aromatic heteropolycyclic compounds
External Descriptors: N-acyl-amino acid (CHEBI:5847)

Targets

Property	Measurement	pH	Temperature (°C)	References
IC 50 (nM)	380	7.4	30	16279780

Details1. 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

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. [PubMed:10047461]
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. [PubMed:10430100]
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]
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. [PubMed:10496350]
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. [PubMed:10499608]
Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352]
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. [PubMed:18773878]
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. [PubMed:10598555]
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. [PubMed:10592235]

Details2. Folylpolyglutamate synthase, mitochondrial

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. [PubMed:11916544]

Drug created on June 13, 2005 07:24 / Updated on April 13, 2019 21:08

Raltitrexed

Identification

Structure for Raltitrexed (DB00293)

Pharmacology

Interactions

References

Clinical Trials

Pharmacoeconomics

Properties

Spectra

Taxonomy

Targets

References

References