ContaminantDB: Methotrexate

Identification Taxonomy Biological Properties Physical Properties Toxicity Profile Spectra Concentrations Links References Targets (11)XML

Record Information

Version

1.0

Creation Date

2009-07-03 22:10:49 UTC

Update Date

2026-04-06 04:10:44 UTC

Accession Number

CHEM002067

Identification

Common Name

Methotrexate

Class

Small Molecule

Description

Methotrexate is only found in individuals that have used or taken this drug. It is an antineoplastic antimetabolite with immunosuppressant properties. It is an inhibitor of tetrahydrofolate dehydrogenase and prevents the formation of tetrahydrofolate, necessary for synthesis of thymidylate, an essential component of DNA. [PubChem]Methotrexate anti-tumor activity is a result of the inhibition of folic acid reductase, leading to inhibition of DNA synthesis and inhibition of cellular replication. The mechanism involved in its activity against rheumatoid arthritis is not known.

Contaminant Sources

HMDB Contaminants - Urine
IARC Carcinogens Group 3
STOFF IDENT Compounds
T3DB toxins
ToxCast & Tox21 Chemicals

Contaminant Type

Abortifacient Agent
Abortifacient Agent, Nonsteroidal
Amide
Amine
Antimetabolite
Antimetabolite, Antineoplastic
Antineoplastic Agent
Antirheumatic Agent
Dermatologic Agent
Drug
Enzyme Inhibitor
Ester
Folic Acid Antagonist
Immunosuppressive Agent
Metabolite
Nucleic Acid Synthesis Inhibitor
Organic Compound
Synthetic Compound

Chemical Structure

MOL SDF PDB SMILES InChI

Synonyms

Value	Source
4-Amino-10-methylfolic acid	ChEBI
4-Amino-N(10)-methylpteroylglutamic acid	ChEBI
Emtexate	ChEBI
Ledertrexate	ChEBI
Methotrexatum	ChEBI
Metotrexato	ChEBI
MTX	ChEBI
N-[4-[[(2,4-Diamino-6-pteridinyl)methyl]methylamino]benzoyl]-L-glutamic acid	ChEBI
Rheumatrex	ChEBI
Trexall	ChEBI
Otrexup	Kegg
Xatmep	Kegg
4-Amino-10-methylfolate	Generator
4-Amino-N(10)-methylpteroylglutamate	Generator
Emtexic acid	Generator
Ledertrexic acid	Generator
N-[4-[[(2,4-Diamino-6-pteridinyl)methyl]methylamino]benzoyl]-L-glutamate	Generator
Methotrexic acid	Generator
Amethopterin	HMDB
Amethopterine	HMDB
HDMTX	HMDB
L-Amethopterin	HMDB
Methopterin	HMDB
Methotextrate	HMDB
Methotrexat	HMDB
Methylaminopterin	HMDB
Methylaminopterinum	HMDB
N-Bismethylpteroylglutamic acid	HMDB
Hydrate, methotrexate	HMDB
Methotrexate, disodium salt	HMDB
Methotrexate, sodium salt	HMDB
Methotrexate, (DL)-isomer	HMDB
Sodium, methotrexate	HMDB
Dicesium salt methotrexate	HMDB
Methotrexate hydrate	HMDB
Methotrexate, dicesium salt	HMDB
Mexate	HMDB
Methotrexate sodium	HMDB
Methotrexate, (D)-isomer	HMDB

Chemical Formula

C₂₀H₂₂N₈O₅

Average Molecular Mass

454.439 g/mol

Monoisotopic Mass

454.171 g/mol

CAS Registry Number

59-05-2

IUPAC Name

(2S)-2-[(4-{[(2,4-diaminopteridin-6-yl)methyl](methyl)amino}phenyl)formamido]pentanedioic acid

Traditional Name

methotrexate

SMILES

CN(CC1=CN=C2N=C(N)N=C(N)C2=N1)C1=CC=C(C=C1)C(=O)N[C@@H](CCC(O)=O)C(O)=O

InChI Identifier

InChI=1S/C20H22N8O5/c1-28(9-11-8-23-17-15(24-11)16(21)26-20(22)27-17)12-4-2-10(3-5-12)18(31)25-13(19(32)33)6-7-14(29)30/h2-5,8,13H,6-7,9H2,1H3,(H,25,31)(H,29,30)(H,32,33)(H4,21,22,23,26,27)/t13-/m0/s1

InChI Key

FBOZXECLQNJBKD-ZDUSSCGKSA-N

Chemical Taxonomy

Description

belongs to the class of organic compounds known as glutamic acid and derivatives. Glutamic acid and derivatives 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

Substituents

Glutamic acid or derivatives
Hippuric acid or derivatives
Hippuric acid
N-acyl-alpha-amino acid
N-acyl-alpha amino acid or derivatives
Aminobenzamide
Aminobenzoic acid or derivatives
Pteridine
Benzamide
Benzoic acid or derivatives
Benzoyl
Aniline or substituted anilines
Tertiary aliphatic/aromatic amine
Dialkylarylamine
Aminopyrimidine
Aralkylamine
Benzenoid
Pyrimidine
Pyrazine
Monocyclic benzene moiety
Dicarboxylic acid or derivatives
Heteroaromatic compound
Tertiary amine
Secondary carboxylic acid amide
Carboxamide group
Amino acid
Carboxylic acid
Organoheterocyclic compound
Azacycle
Organic oxygen compound
Primary amine
Carbonyl group
Amine
Organic oxide
Organic nitrogen compound
Organopnictogen compound
Hydrocarbon derivative
Organooxygen compound
Organonitrogen compound
Aromatic heteropolycyclic compound

Molecular Framework

Aromatic heteropolycyclic compounds

External Descriptors

monocarboxylic acid amide (CHEBI:44185 )
dicarboxylic acid (CHEBI:44185 )
pteridines (CHEBI:44185 )

Biological Properties

Status

Detected and Not Quantified

Origin

Exogenous

Cellular Locations

Cytoplasm
Extracellular
Membrane

Biofluid Locations

Not Available

Tissue Locations

Not Available

Pathways

Not Available

Applications

Not Available

Biological Roles

Not Available

Chemical Roles

Not Available

Physical Properties

State

Solid

Appearance

Orange-brown, crystalline powder (3).

Experimental Properties

Property	Value
Melting Point	195°C
Boiling Point	Not Available
Solubility	2600 mg/L

Predicted Properties

Property	Value	Source
Water Solubility	0.17 g/L	ALOGPS
logP	-0.91	ALOGPS
logP	-0.24	ChemAxon
logS	-3.4	ALOGPS
pKa (Strongest Acidic)	3.26	ChemAxon
pKa (Strongest Basic)	1.8	ChemAxon
Physiological Charge	-2	ChemAxon
Hydrogen Acceptor Count	12	ChemAxon
Hydrogen Donor Count	5	ChemAxon
Polar Surface Area	210.54 Å²	ChemAxon
Rotatable Bond Count	9	ChemAxon
Refractivity	119.21 m³·mol⁻¹	ChemAxon
Polarizability	44.54 Å³	ChemAxon
Number of Rings	3	ChemAxon
Bioavailability	0	ChemAxon
Rule of Five	No	ChemAxon
Ghose Filter	Yes	ChemAxon
Veber's Rule	No	ChemAxon
MDDR-like Rule	Yes	ChemAxon

Spectra

Spectrum Type	Description	Splash Key	View
Predicted GC-MS	Predicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, Positive	splash10-0a4i-2224900000-2f01d2daa7d3813c673a	Spectrum
Predicted GC-MS	Predicted GC-MS Spectrum - GC-MS (2 TMS) - 70eV, Positive	splash10-001i-3122290000-fa019cd3d12beee4e641	Spectrum
Predicted GC-MS	Predicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, Positive	Not Available	Spectrum
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-qTof , Positive	splash10-004i-0950000000-ca28d8dfdf780c201716	Spectrum
LC-MS/MS	LC-MS/MS Spectrum - , positive	splash10-0a4i-1819500000-3159955c0d961d305b13	Spectrum
LC-MS/MS	LC-MS/MS Spectrum - , positive	splash10-0a4i-0619400000-9a6d686008b68ac436ba	Spectrum
LC-MS/MS	LC-MS/MS Spectrum - , positive	splash10-004i-2902000000-526ede2e4de609cb3d44	Spectrum
LC-MS/MS	LC-MS/MS Spectrum - 50V, Positive	splash10-004i-0900000000-cef8960392ea13368437	Spectrum
LC-MS/MS	LC-MS/MS Spectrum - 40V, Positive	splash10-056r-0902000000-aab26d4a02edcef1a8c4	Spectrum
LC-MS/MS	LC-MS/MS Spectrum - 35V, Negative	splash10-0xy4-1813900000-07af6d8890331278a198	Spectrum
LC-MS/MS	LC-MS/MS Spectrum - 30V, Positive	splash10-0a4i-0209000000-fab54dfaa503a46c63b7	Spectrum
LC-MS/MS	LC-MS/MS Spectrum - 20V, Positive	splash10-0a4i-0009100000-8978b68caba7882f8318	Spectrum
LC-MS/MS	LC-MS/MS Spectrum - 35V, Positive	splash10-0a4i-0309000000-6f0d42ae8490e1a1816c	Spectrum
LC-MS/MS	LC-MS/MS Spectrum - 10V, Positive	splash10-0a4i-0001900000-e7bd0358d640d5e7461f	Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 10V, Positive	splash10-0a4i-0213900000-1fa0d7d6d64dbadf542d	Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 20V, Positive	splash10-056r-0937400000-de89bffee2deae003f47	Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 40V, Positive	splash10-056r-0921000000-3abec3045f5ab5af7a2a	Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 10V, Negative	splash10-0udi-0001900000-a87855dc4c7855304f61	Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 20V, Negative	splash10-0pc0-0355900000-b18b5db2a15dc639aa07	Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 40V, Negative	splash10-052f-6932000000-10efc16714372e5c2251	Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 10V, Negative	splash10-0w2l-0015900000-a2d8b53f29122f89e0ff	Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 20V, Negative	splash10-03di-1414900000-98c6c8566f3e992eefea	Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 40V, Negative	splash10-0udi-3932500000-6c263dd73e3456639a66	Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 10V, Positive	splash10-0a4i-0007900000-8cba12ac60841dc8166e	Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 20V, Positive	splash10-0a4i-1209000000-4b85d18f5dea93f16c31	Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 40V, Positive	splash10-004i-1912000000-ea76f7a5ebd9b44acbea	Spectrum
MS	Mass Spectrum (Electron Ionization)	splash10-0fai-6900000000-25b0e287457fb3845ef4	Spectrum
1D NMR	1H NMR Spectrum	Not Available	Spectrum
1D NMR	13C NMR Spectrum	Not Available	Spectrum
1D NMR	13C NMR Spectrum	Not Available	Spectrum
1D NMR	1H NMR Spectrum	Not Available	Spectrum
1D NMR	13C NMR Spectrum	Not Available	Spectrum
1D NMR	1H NMR Spectrum	Not Available	Spectrum
1D NMR	13C NMR Spectrum	Not Available	Spectrum
1D NMR	1H NMR Spectrum	Not Available	Spectrum
1D NMR	13C NMR Spectrum	Not Available	Spectrum
1D NMR	1H NMR Spectrum	Not Available	Spectrum
1D NMR	13C NMR Spectrum	Not Available	Spectrum
1D NMR	1H NMR Spectrum	Not Available	Spectrum
1D NMR	13C NMR Spectrum	Not Available	Spectrum
1D NMR	1H NMR Spectrum	Not Available	Spectrum
1D NMR	13C NMR Spectrum	Not Available	Spectrum
1D NMR	1H NMR Spectrum	Not Available	Spectrum
1D NMR	13C NMR Spectrum	Not Available	Spectrum
1D NMR	1H NMR Spectrum	Not Available	Spectrum
1D NMR	13C NMR Spectrum	Not Available	Spectrum
1D NMR	1H NMR Spectrum	Not Available	Spectrum
1D NMR	13C NMR Spectrum	Not Available	Spectrum
1D NMR	1H NMR Spectrum	Not Available	Spectrum

Toxicity Profile

Route of Exposure

Inhalation (2); dermal (2); intravenous (2) Oral absorption is dose dependent in adults and leukemic pediatric patients. In adults, peak serum levels are reached within one to two hours. At doses of 30 mg/m^2 or less, methotrexate is generally well absorbed with a mean bioavailability of 60%. At doses greater than 80 mg/m^2, the absorption of the doses is significantly less due to a saturation effect.

Mechanism of Toxicity

Methotrexate anti-tumor activity is a result of the inhibition of folic acid reductase, leading to inhibition of DNA synthesis and inhibition of cellular replication. The mechanism involved in its activity against rheumatoid arthritis is not known.

Metabolism

After absorption, methotrexate undergoes hepatic and intracellular metabolism to form methotrexate polyglutamate, metabolites which by hydrolysis may be converted back to methotrexate. Methotrexate polyglutamates inhibit dihydrofolate reductase and thymidylate synthetase. Small amounts of these polyglutamate metabolites may remain in tissues for extended periods; the retention and prolonged action of these active metabolites vary among different cells, tissues, and tumors. In addition, small amounts of methotrexate polyglutamate may be converted to 7-hydroxymethotrexate; accumulation of this metabolite may become substantial following administration of high doses of methotrexate, since the aqueous solubility of 7-hydroxymethotrexate is threefold to fivefold lower than that of the parent compound. Following oral administration of methotrexate, the drug also is partially metabolized by the intestinal flora. Renal excretion is the primary route of elimination, and is dependent upon dosage and route of administration (4). Route of Elimination: Renal excretion is the primary route of elimination and is dependent upon dosage and route of administration. IV administration, 80% to 90% of the administered dose is excreted unchanged in the urine within 24 hours. There is limited biliary excretion amounting to 10% or less of the administered dose. Half Life: Low doses (less than 30 mg/m^2): 3 to 10 hours; High doses: 8 to 15 hours.

Toxicity Values

LD50: 43 mg/kg (Oral, Rat) (1)

Lethal Dose

Not Available

Carcinogenicity (IARC Classification)

3, not classifiable as to its carcinogenicity to humans. (7)

Uses/Sources

Methotrexate is indicated in the treatment of gestational choriocarcinoma, chorioadenoma destruens and hydatidiform mole. In acute lymphocytic leukemia, methotrexate is indicated in the prophylaxis of meningeal leukemia and is used in maintenance therapy in combination with other chemotherapeutic agents. Methotrexate is also indicated in the treatment of meningeal leukemia. Methotrexate is used alone or in combination with other anticancer agents in the treatment of breast cancer, epidermoid cancers of the head and neck, advanced mycosis fungoides (cutaneous T cell lymphoma), and lung cancer, particularly squamous cell and small cell types. Methotrexate is also used in combination with other chemotherapeutic agents in the treatment of advanced stage non-Hodgkin's lymphomas. Methotrexate is indicated in the symptomatic control of severe, recalcitrant, disabling psoriasis. Methotrexate is indicated in the management of selected adults with severe, active rheumatoid arthritis (ACR criteria), or children with active polyarticular-course juvenile rheumatoid arthritis.

Minimum Risk Level

Not Available

Health Effects

A small percentage of patients develop hepatitis, and there is an increased risk of pulmonary fibrosis where dry cough can be an important sign. The higher doses of methotrexate often used in cancer chemotherapy can cause toxic effects to the rapidly-dividing cells of bone marrow and gastrointestinal mucosa. The resulting myelosuppression and mucositis are often prevented (termed Leucovorin "rescue"- as this is the folic acid based drug used) (8).

Symptoms

Symptoms of overdose include bone marrow suppression and gastrointestinal toxicity.

Treatment

Administer charcoal as a slurry. Consider gastric lavage after ingestion of a potentially life-threatening amount of poison if it can be performed soon after ingestion (generally within 1 hour). Protect airway by placement in Trendelenburg and left lateral decubitus position or by endotracheal intubation. Control any seizures first. Glucarpidase has been used intravenously in combination with thymidine and leucovorin to treat methotrexate toxicity. (10)

Concentrations

Not Available

External Links

DrugBank ID

DB00563

HMDB ID

HMDB0014703

FooDB ID

Not Available

Phenol Explorer ID

Not Available

KNApSAcK ID