RALTITREXED DISODIUM

Possibly Marketed Outside US

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C21H20N4O6S.2Na
Molecular Weight	502.451
Optical Activity	UNSPECIFIED
Defined Stereocenters	1 / 1
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

[Na+].[Na+].CN(CC1=CC2=C(C=C1)N=C(C)NC2=O)C3=CC=C(S3)C(=O)N[C@@H](CCC([O-])=O)C([O-])=O

InChI

InChIKey=HYYVJHYAMGPPLX-CKUXDGONSA-L

InChI=1S/C21H22N4O6S.2Na/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);;/q;2*+1/p-2/t15-;;/m0../s1

HIDE SMILES / InChI

Molecular Formula	Na
Molecular Weight	22.98976928
Charge	1
Count

Stereochemistry	ACHIRAL
Additional Stereochemistry	No
Defined Stereocenters	0 / 0
E/Z Centers	0
Optical Activity	NONE

Molecular Formula	C21H20N4O6S
Molecular Weight	456.472
Charge	-2
Count

Stereochemistry	ABSOLUTE
Additional Stereochemistry	No
Defined Stereocenters	1 / 1
E/Z Centers	0
Optical Activity	UNSPECIFIED

Description
Sources: https://www.drugbank.ca/drugs/DB00293
Curator's Comment: Description was created based on several sources, including https://www.medicines.org.uk/emc/medicine/2307 https://www.ncbi.nlm.nih.gov/pubmed/21148615

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. 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. Raltitrexed is used for the treatment of malignant neoplasm of colon and rectum. Although raltitrexed is not approved by the US FDA, the drug was licensed in Canada and some European countries.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Thymidylate synthase 33 Target ID: CHEMBL1952 Sources: https://www.drugbank.ca/drugs/DB00293	Inhibitor 8504		530.0 nM [IC50]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Advanced colorectal cancer 8 Sources: http://www.bccancer.bc.ca/drug-database-site/Drug%20Index/Raltitrexed_monograph_1June2013_formatted.pdf	Palliative		Approved 8583	Tomudex Approved Use The palliative treatment of advanced colorectal cancer where 5-Fluorouracil and folinic acid based regimens are either not tolerated or inappropriate. Launch Date 2000

C_max

Value	Dose	Co-administered	Analyte	Population
736.8 ng/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/9619761	3 mg/m² single, intravenous dose: 3 mg/m² route of administration: Intravenous experiment type: SINGLE co-administered:		RALTITREXED plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
567.1 ng/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/9820178	3 mg/m² 1 times / day other, intravenous dose: 3 mg/m² route of administration: Intravenous experiment type: OTHER co-administered:		RALTITREXED blood	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

AUC

Value	Dose	Co-administered	Analyte	Population
2341.7 ng × h/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/9619761	3 mg/m² single, intravenous dose: 3 mg/m² route of administration: Intravenous experiment type: SINGLE co-administered:		RALTITREXED plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
1547.9 ng × h/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/9820178	3 mg/m² 1 times / day other, intravenous dose: 3 mg/m² route of administration: Intravenous experiment type: OTHER co-administered:		RALTITREXED blood	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

T_1/2

Value	Dose	Co-administered	Analyte	Population
12 min EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/9619761	3 mg/m² single, intravenous dose: 3 mg/m² route of administration: Intravenous experiment type: SINGLE co-administered:		RALTITREXED plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
1.82 h EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/9820178	3 mg/m² 1 times / day other, intravenous dose: 3 mg/m² route of administration: Intravenous experiment type: OTHER co-administered:		RALTITREXED blood	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

F_unbound

Value	Dose	Co-administered	Analyte	Population
7% OTHER GOV https://www.pfizer.ca/sites/default/files/201710/TOMUDEX_PM.pdf			RALTITREXED plasma	Homo sapiens population: UNKNOWN age: UNKNOWN sex: UNKNOWN food status: UNKNOWN

Doses

Dose	Population	Adverse events
4.5 mg/m2 1 times / 3 weeks multiple, intravenous Highest studied dose\|MTD Dose: 4.5 mg/m2, 1 times / 3 weeks Route: intravenous Route: multiple Dose: 4.5 mg/m2, 1 times / 3 weeks Sources: https://pubmed.ncbi.nlm.nih.gov/10499608/ https://pubmed.ncbi.nlm.nih.gov/11432631/	unhealthy, Median age 55.5 years Health Status: unhealthy Age Group: Median age 55.5 years Sex: M+F Sources: https://pubmed.ncbi.nlm.nih.gov/10499608/ https://pubmed.ncbi.nlm.nih.gov/11432631/	DLT: Asthenia, Granulocytopenia... Other AEs: Leukocytopenia, Nausea... Dose limiting toxicities: Asthenia (grade 3, 33.3%) Granulocytopenia (grade 4, 11.1%) Fatigue (grade 3, 11.1%) Other AEs: Leukocytopenia (grade 3, 11.1%) Nausea (grade 3, 11.1%) Aspartate aminotransferase increased (grade 3, 11.1%) Alanine aminotransferase increase (grade 3, 33.3%) Bilirubin elevated (grade 3-4, 11.1%) Sources: https://pubmed.ncbi.nlm.nih.gov/10499608/ https://pubmed.ncbi.nlm.nih.gov/11432631/
3.5 mg/m2 1 times / 3 weeks multiple, intravenous Studied dose Dose: 3.5 mg/m2, 1 times / 3 weeks Route: intravenous Route: multiple Dose: 3.5 mg/m2, 1 times / 3 weeks Sources: https://pubmed.ncbi.nlm.nih.gov/10499608/ https://pubmed.ncbi.nlm.nih.gov/11432631/	unhealthy, Median age 55.5 years Health Status: unhealthy Age Group: Median age 55.5 years Sex: M+F Sources: https://pubmed.ncbi.nlm.nih.gov/10499608/ https://pubmed.ncbi.nlm.nih.gov/11432631/	DLT: Asthenia... Other AEs: Decreased hemoglobin... Dose limiting toxicities: Asthenia (grade 3, 15.4%) Other AEs: Decreased hemoglobin (grade 3, 7.7%) Sources: https://pubmed.ncbi.nlm.nih.gov/10499608/ https://pubmed.ncbi.nlm.nih.gov/11432631/
4 mg/m2 1 times / 3 weeks multiple, intravenous Studied dose Dose: 4 mg/m2, 1 times / 3 weeks Route: intravenous Route: multiple Dose: 4 mg/m2, 1 times / 3 weeks Sources: https://pubmed.ncbi.nlm.nih.gov/10499608/ https://pubmed.ncbi.nlm.nih.gov/11432631/	unhealthy, Median age 55.5 years Health Status: unhealthy Age Group: Median age 55.5 years Sex: M+F Sources: https://pubmed.ncbi.nlm.nih.gov/10499608/ https://pubmed.ncbi.nlm.nih.gov/11432631/	DLT: Granulocytopenia, Bilirubin elevated... Dose limiting toxicities: Granulocytopenia (grade 4, 16.7%) Bilirubin elevated (grade 4, 8.3%) Sources: https://pubmed.ncbi.nlm.nih.gov/10499608/ https://pubmed.ncbi.nlm.nih.gov/11432631/
2.5 mg/m2 1 times / 3 weeks multiple, intravenous Studied dose Dose: 2.5 mg/m2, 1 times / 3 weeks Route: intravenous Route: multiple Dose: 2.5 mg/m2, 1 times / 3 weeks Sources: https://pubmed.ncbi.nlm.nih.gov/11432631/	unhealthy, Median age 62 years Health Status: unhealthy Age Group: Median age 62 years Sex: M+F Sources: https://pubmed.ncbi.nlm.nih.gov/11432631/	DLT: Neutropenia... Dose limiting toxicities: Neutropenia (grade 4, 66.7%) Sources: https://pubmed.ncbi.nlm.nih.gov/11432631/
3 mg/m2 1 times / 3 weeks multiple, intravenous Studied dose Dose: 3 mg/m2, 1 times / 3 weeks Route: intravenous Route: multiple Dose: 3 mg/m2, 1 times / 3 weeks Sources: http://www.bccancer.bc.ca/drug-database-site/Drug%20Index/Raltitrexed_monograph_1June2013_formatted.pdf https://www.pfizer.ca/sites/default/files/201710/TOMUDEX_PM.pdf	unhealthy Health Status: unhealthy Sex: M+F Sources: http://www.bccancer.bc.ca/drug-database-site/Drug%20Index/Raltitrexed_monograph_1June2013_formatted.pdf https://www.pfizer.ca/sites/default/files/201710/TOMUDEX_PM.pdf	DLT: Leukocytopenia, Transaminases increased... Dose limiting toxicities: Leukocytopenia (grade 3-4, 12.9%) Transaminases increased (grade 3-4, 10.1%) Sources: http://www.bccancer.bc.ca/drug-database-site/Drug%20Index/Raltitrexed_monograph_1June2013_formatted.pdf https://www.pfizer.ca/sites/default/files/201710/TOMUDEX_PM.pdf
3 mg/m2 1 times / 3 weeks multiple, intravenous Studied dose Dose: 3 mg/m2, 1 times / 3 weeks Route: intravenous Route: multiple Dose: 3 mg/m2, 1 times / 3 weeks Sources: https://www.pfizer.ca/sites/default/files/201710/TOMUDEX_PM.pdf	unhealthy Health Status: unhealthy Sex: M+F Sources: https://www.pfizer.ca/sites/default/files/201710/TOMUDEX_PM.pdf	Other AEs: Nausea and vomiting, Diarrhea... Other AEs: Nausea and vomiting (grade 3-4, 11.6%) Diarrhea (grade 3-4, 11.1%) Constipation (grade 3-4, 2%) Oral soft tissue conditions (grade 3-4, 2.1%) Pain (grade 3-4, 7.3%) Infection (grade 3-4, 5%) Hemoglobin decreased (grade 3-4, 6.5%) Thrombocytopenia (grade 3-4, 3.5%) Blood bilirubin decreased (grade 3-4, 2.2%) Sources: https://www.pfizer.ca/sites/default/files/201710/TOMUDEX_PM.pdf

AEs

Overview

CYP3A4	CYP2C9	CYP2D6	hERG

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
BSEP 550 MRP4 290 MRP3 246 MRP1 116	MRP4 91 OATP1A4 2

Drug as perpetrator

Target	Modality	Activity
BSEP 554	inhibitor 4027 Sources: https://academic.oup.com/toxsci/article/136/1/216/1653420 Page: -	no [IC50 133 uM]
MRP1 232	inhibitor 4027 Sources: https://academic.oup.com/toxsci/article/136/1/216/1653420 Page: -	no [IC50 133 uM]
MRP3 326	inhibitor 4027 Sources: https://academic.oup.com/toxsci/article/136/1/216/1653420 Page: -	no [IC50 133 uM]
MRP4 345	inhibitor 4027 Sources: https://academic.oup.com/toxsci/article/136/1/216/1653420 Page: -	no [IC50 133 uM]

Drug as victim

Target	Modality	Activity	Metabolite	Clinical evidence
MRP4 91	substrate 4014 Sources: https://www.sciencedirect.com/science/article/abs/pii/S0022354917302769 Page: -	yes [Km 43.7 uM]
OATP1A4 2	substrate 4014 Sources: https://www.sciencedirect.com/science/article/abs/pii/S0022354917302769 Page: -	yes

PubMed

Title	Date	PubMed
A rapid and systematic review of the evidence for the clinical effectiveness and cost-effectiveness of irinotecan, oxaliplatin and raltitrexed for the treatment of advanced colorectal cancer.	2001	11990245
Characterization and drug sensitivity of four newly established colon adenocarcinoma cell lines to antifolate inhibitors of thymidylate synthase.	2001	11589301
A phase I study of raltitrexed (Tomudex) combined with carmofur in metastatic colorectal cancer.	2001	11528249
Molecular and cellular biology of the human reduced folate carrier.	2001	11525381
[New chemotherapies for colorectal cancer treatment].	2001 Apr	11449145
Safe administration of irinotecan, oxaliplatin and raltitrexed in a DPD-deficient patient with metastatic colon cancer.	2001 Apr	11398894
Chemotherapy in elderly patients with colorectal cancer.	2001 Apr	11398873
The role of irinotecan and oxaliplatin in the treatment of advanced colorectal cancer.	2001 Apr	11346931
[Oxaliplatin in combination with non fluoropyrimidine drugs in colorectal cancer].	2001 Aug	11567912
[Assessment of the cost of first line chemotherapy in metastatic colorectal cancer. Preliminary results in the FFCD 9601 trial].	2001 Aug-Sep	11598535
Raltitrexed/5-fluorouracil-based combination chemotherapy regimens in anticancer therapy.	2001 Jul	11459994
Pharmacogenomic dissection of resistance to thymidylate synthase inhibitors.	2001 Jul 15	11454699
New therapies, new directions: advances in the systemic treatment of metastatic colorectal cancer.	2001 May	11905784
Characterization of a thymidylate synthase (TS)-inducible cell line: a model system for studying sensitivity to TS- and non-TS-targeted chemotherapies.	2001 Nov	11705873
Single nucleotide polymorphisms in the human reduced folate carrier: characterization of a high-frequency G/A variant at position 80 and transport properties of the His(27) and Arg(27) carriers.	2001 Nov	11705857
Preoperative chemoradiation with raltitrexed ('Tomudex') for T2/N+ and T3/N+ rectal cancers: a phase I study.	2001 Nov	11597383
[Colorectal cancer: irinotecan in combination with newer drugs].	2001 Nov-Dec	11995705
[Oxaliplatin: combinations with thymidylate synthetase inhibitors: two consecutive phase II studies].	2001 Nov-Dec	11995701
Oxaliplatin and raltitrexed in the treatment of inoperable malignant pleural mesothelioma: results of a pilot study.	2001 Nov-Dec	11989592
[New therapeutic options in chemotherapy of advanced colorectal cancer].	2001 Oct 15	11715331
Phase I clinical and pharmacogenetic trial of irinotecan and raltitrexed administered every 21 days to patients with cancer.	2001 Oct 15	11600611
Antifolate resistance and its circumvention by new analogues.	2001 Sep	11774738
Multicenter phase II trial of dose-fractionated irinotecan in patients with advanced colorectal cancer failing oxaliplatin-based first-line combination chemotherapy.	2001 Sep	11697839
[Recent aspects of palliative treatment of metastasized colorectal carcinoma].	2001 Sep 15	11603115
[Intraoperative radiotherapy (IORT) in the treatment of rectal cancer].	2001 Sep-Oct	11975411
Present indications for adjuvant therapy in resectable rectal cancer.	2001 Sep-Oct	11975405
[Raltitrexed and oxaliplatin in colorectal cancer: in vitro and in vivo study of a synergistic cytostatic combination].	2002	12424937
Chemotherapy in colorectal cancer: new options and new challenges.	2002	12421732
Cisplatin, raltitrexed, levofolinic acid and 5-fluorouracil in locally advanced or metastatic squamous cell carcinoma of the head and neck: a phase II randomized study.	2002	12381902
[The rare manifestation of soft tissue metastasis in colorectal cancer].	2002	12202897
Conjoint analysis of a new Chemotherapy: willingness to pay and preference for the features of raltitrexed versus standard therapy in advanced Colorectal Cancer.	2002	12201796
Pemetrexed for diffuse malignant pleural mesothelioma.	2002 Apr	12023790
Second-Line Treatment of Advanced Colorectal Cancer with a Biweekly Oxaliplatin plus Irinotecan Combination Regimen.	2002 Aug	12232488
Raltitrexed (tomudex) administration in patients failing multiple prior chemotherapy regimens in advanced colorectal cancer: a pilot study.	2002 Feb	12003191
Nucleoside transport inhibitors, dipyridamole and p-nitrobenzylthioinosine, selectively potentiate the antitumor activity of NB1011.	2002 Jan	11914638
Randomized multicenter phase II trial of oxaliplatin plus irinotecan versus raltitrexed as first-line treatment in advanced colorectal cancer.	2002 Jan 1	11773166
Baseline quality of life predicts survival in patients with advanced colorectal cancer.	2002 Jul	12091066
A rationale for the clinical development of the thymidylate synthase inhibitor ZD9331 in ovarian and other solid tumours.	2002 Jul 18	12084463
Advanced colorectal cancer treatment in Europe: what have we achieved?	2002 Jun	12045457
Raltitrexed in the treatment of elderly patients with advanced colorectal cancer: an active and low toxicity regimen.	2002 Jun	12044507
Oxaliplatin plus raltitrexed and leucovorin-modulated 5-fluorouracil i.v. bolus: a salvage regimen for colorectal cancer patients.	2002 Jun 17	12085178
Costs and consequences of different chemotherapy regimens in metastatic colorectal cancer.	2002 Jun 5	12087450
Which endpoints should we use in evaluating the use of novel fluoropyrimidine regimens in colorectal cancer?	2002 Jun 5	12087448
Why hasn't the National Institute been 'NICE' to patients with colorectal cancer? National Institute of Clinical Excellence.	2002 Jun 5	12087447
Sequence-dependent effects of ZD1839 ('Iressa') in combination with cytotoxic treatment in human head and neck cancer.	2002 Mar 4	11875748
Raltitrexed plus oxaliplatin (TOMOX) as first-line chemotherapy for metastatic colorectal cancer. A phase II study of the Italian Group for the Study of Gastrointestinal Tract Carcinomas (GISCAD).	2002 May	12075739
Oxaliplatin: results in colorectal carcinoma.	2002 Oct	12398998
Phase I and pharmacokinetic study of irinotecan in combination with raltitrexed.	2002 Oct	12357298
Ex vivo stimulation of renal transport of the cytostatic drugs methotrexate, cisplatin, topotecan (Hycamtin) and raltitrexed (Tomudex) by dexamethasone, T3 and EGF in intact human and rat kidney tissue and in human renal cell carcinoma.	2002 Sep	12202944
Raltitrexed treatment promotes systemic inflammatory reaction in patients with colorectal carcinoma.	2002 Sep 9	12237767

Patents

Sample Use Guides

In Vivo Use Guide

The recommended dose is 3 mg/m2 given intravenously, as a single short, intravenous infusion in 50 to 250 ml of either 0.9% sodium chloride solution or 5% dextrose (glucose) solution. It is recommended that the infusion is given over a 15 minute period. Other drugs should not be mixed with 'Tomudex' (raltitrexed) in the same infusion container. In the absence of toxicity, treatment may be repeated every 3 weeks. Dose escalation above 3 mg/m2 is not recommended, since higher doses have been associated with an increased incidence of life-threatening or fatal toxicity.

Route of Administration: Intravenous

In Vitro Use Guide

In WiDr colon adenocarcinoma cells the cytotoxicity of 1.0 uM Raltitrexed (4 h) varied from 0% to >99% within the reported range of human serum thymidine concentrations from 500 to <50 nM, respectively.

Substance Class	Chemical Created by `admin` on `Mon Mar 31 22:02:19 GMT 2025` Edited by `admin` on `Mon Mar 31 22:02:19 GMT 2025`
Record UNII	50VZN4BPUK
Record Status	`Validated (UNII)`
Record Version

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Name

Type

Language

RALTITREXED DISODIUM

Common Name

English

L-GLUTAMIC ACID, N-((5-(((3,4-DIHYDRO-2-METHYL-4-OXO-6-QUINAZOLINYL)METHYL)METHYLAMINO)-2-THIENYL)CARBONYL)-, DISODIUM SALT

Preferred Name

English

Raltitrexed disodium [WHO-DD]

Common Name

English

Classification Tree Code System Code

NCI_THESAURUS

C2021