METHOTREXATE SODIUM

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C20H20N8O5.2Na
Molecular Weight	498.4037
Optical Activity	UNSPECIFIED
Defined Stereocenters	1 / 1
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

CN(Cc1cnc2c(c(N)[nH]c(=N)n2)n1)c3ccc(cc3)C(=O)N[C@@]([H])(CCC(=O)[O-])C(=O)[O-].[Na+].[Na+]

InChI

InChIKey=DASQOOZCTWOQPA-GXKRWWSZSA-L

InChI=1S/C20H22N8O5.2Na/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);;/q;2*+1/p-2/t13-;;/m0../s1

HIDE SMILES / InChI

Molecular Formula	Na
Molecular Weight	22.9898
Charge	1
Count

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

Molecular Formula	C20H20N8O5
Molecular Weight	452.4242
Charge	-2
Count

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

Description
Sources: http://www.drugbank.ca/drugs/DB00563
Curator's Comment:: Description was created based on several sources, including https://www.drugs.com/methotrexate.html

Methotrexate is an antineoplastic anti-metabolite. Anti-metabolites masquerade as purine or pyrimidine - which become the building blocks of DNA. They prevent these substances becoming incorporated in to DNA during the "S" phase (of the cell cycle), stopping normal development and division. Methotrexate inhibits folic acid reductase which is responsible for the conversion of folic acid to tetrahydrofolic acid. At two stages in the biosynthesis of purines and at one stage in the synthesis of pyrimidines, one-carbon transfer reactions occur which require specific coenzymes synthesized in the cell from tetrahydrofolic acid. Tetrahydrofolic acid itself is synthesized in the cell from folic acid with the help of an enzyme, folic acid reductase. Methotrexate looks a lot like folic acid to the enzyme, so it binds to it quite strongly and inhibits the enzyme. Thus, DNA synthesis cannot proceed because the coenzymes needed for one-carbon transfer reactions are not produced from tetrahydrofolic acid because there is no tetrahydrofolic acid. Methotrexate selectively affects the most rapidly dividing cells (neoplastic and psoriatic cells). 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.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Potency
Dihydrofolate reductase 55 Target ID: CHEMBL202 Sources: http://www.drugbank.ca/drugs/DB00563	Inhibitor 7709	5.19 pM [Ki]
Serum paraoxonase/arylesterase 1 30 Target ID: CHEMBL3167 Sources: https://www.ncbi.nlm.nih.gov/pubmed/26458405	Inhibitor 7709	0.18 mM [IC50]
HT-1080 4 Target ID: CHEMBL614580 Sources: https://www.ncbi.nlm.nih.gov/pubmed/11555609	Inhibitor 7709	15.0 nM [IC50]

Conditions

Condition	Modality	Highest Phase	Product
Rheumatoid arthritis 294 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/204824s004lbl.pdf	Primary	Approved 8003	OTREXUP Approved Use Otrexup is a folate analog metabolic inhibitor indicated for the: • Management of patients with severe, active rheumatoid arthritis (RA) and polyarticular juvenile idiopathic arthritis (pJIA), who are intolerant of or had an inadequate response to first-line therapy • Symptomatic control of severe, recalcitrant, disabling psoriasis in adults who are not adequately responsive to other forms of therapy Launch Date -5.36543986E11
Gestational choriocarcinoma 4 Sources: https://www.drugs.com/pro/methotrexate-injection.html	Primary	Approved 8003	TREXALL Approved Use Neoplastic Diseases Methotrexate, USP is indicated in the treatment of gestational choriocarcinoma, chorioadenoma destruens and hydatidiform mole. In acute lymphocytic leukemia, methotrexate, USP is indicated in the prophylaxis of meningeal leukemia and is used in maintenance therapy in combination with other chemotherapeutic agents. Methotrexate, USP is also indicated in the treatment of meningeal leukemia. Methotrexate, USP 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, USP is also used in combination with other chemotherapeutic agents in the treatment of advanced stage non-Hodgkin's lymphomas. Methotrexate, USP in high doses followed by leucovorin rescue in combination with other chemotherapeutic agents is effective in prolonging relapse-free survival in patients with non-metastatic osteosarcoma who have undergone surgical resection or amputation for the primary tumor. Psoriasis Methotrexate, USP is indicated in the symptomatic control of severe, recalcitrant, disabling psoriasis that is not adequately responsive to other forms of therapy, but only when the diagnosis has been established, as by biopsy and/or after dermatologic consultation. It is important to ensure that a psoriasis "flare" is not due to an undiagnosed concomitant disease affecting immune responses. Rheumatoid Arthritis including Polyarticular-Course Juvenile Rheumatoid Arthritis Methotrexate, USP is indicated in the management of selected adults with severe, active rheumatoid arthritis (ACR criteria), or children with active polyarticular-course juvenile rheumatoid arthritis, who have had an insufficient therapeutic response to, or are intolerant of, an adequate trial of first-line therapy including full dose non-steroidal anti-inflammatory agents (NSAIDs). Launch Date 9.8504638E11
Breast cancer 411 Sources: https://www.drugs.com/pro/methotrexate-injection.html	Primary	Approved 8003	TREXALL Approved Use Neoplastic Diseases Methotrexate, USP is indicated in the treatment of gestational choriocarcinoma, chorioadenoma destruens and hydatidiform mole. In acute lymphocytic leukemia, methotrexate, USP is indicated in the prophylaxis of meningeal leukemia and is used in maintenance therapy in combination with other chemotherapeutic agents. Methotrexate, USP is also indicated in the treatment of meningeal leukemia. Methotrexate, USP 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, USP is also used in combination with other chemotherapeutic agents in the treatment of advanced stage non-Hodgkin's lymphomas. Methotrexate, USP in high doses followed by leucovorin rescue in combination with other chemotherapeutic agents is effective in prolonging relapse-free survival in patients with non-metastatic osteosarcoma who have undergone surgical resection or amputation for the primary tumor. Psoriasis Methotrexate, USP is indicated in the symptomatic control of severe, recalcitrant, disabling psoriasis that is not adequately responsive to other forms of therapy, but only when the diagnosis has been established, as by biopsy and/or after dermatologic consultation. It is important to ensure that a psoriasis "flare" is not due to an undiagnosed concomitant disease affecting immune responses. Rheumatoid Arthritis including Polyarticular-Course Juvenile Rheumatoid Arthritis Methotrexate, USP is indicated in the management of selected adults with severe, active rheumatoid arthritis (ACR criteria), or children with active polyarticular-course juvenile rheumatoid arthritis, who have had an insufficient therapeutic response to, or are intolerant of, an adequate trial of first-line therapy including full dose non-steroidal anti-inflammatory agents (NSAIDs). Launch Date 9.8504638E11
Lung cancer 66 Sources: https://www.drugs.com/pro/methotrexate-injection.html	Primary	Approved 8003	TREXALL Approved Use Neoplastic Diseases Methotrexate, USP is indicated in the treatment of gestational choriocarcinoma, chorioadenoma destruens and hydatidiform mole. In acute lymphocytic leukemia, methotrexate, USP is indicated in the prophylaxis of meningeal leukemia and is used in maintenance therapy in combination with other chemotherapeutic agents. Methotrexate, USP is also indicated in the treatment of meningeal leukemia. Methotrexate, USP 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, USP is also used in combination with other chemotherapeutic agents in the treatment of advanced stage non-Hodgkin's lymphomas. Methotrexate, USP in high doses followed by leucovorin rescue in combination with other chemotherapeutic agents is effective in prolonging relapse-free survival in patients with non-metastatic osteosarcoma who have undergone surgical resection or amputation for the primary tumor. Psoriasis Methotrexate, USP is indicated in the symptomatic control of severe, recalcitrant, disabling psoriasis that is not adequately responsive to other forms of therapy, but only when the diagnosis has been established, as by biopsy and/or after dermatologic consultation. It is important to ensure that a psoriasis "flare" is not due to an undiagnosed concomitant disease affecting immune responses. Rheumatoid Arthritis including Polyarticular-Course Juvenile Rheumatoid Arthritis Methotrexate, USP is indicated in the management of selected adults with severe, active rheumatoid arthritis (ACR criteria), or children with active polyarticular-course juvenile rheumatoid arthritis, who have had an insufficient therapeutic response to, or are intolerant of, an adequate trial of first-line therapy including full dose non-steroidal anti-inflammatory agents (NSAIDs). Launch Date 9.8504638E11

C_max

Value	Dose	Co-administered	Analyte	Population
1.205 μM DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/205776s000lbl.pdf	20 mg/m² single, oral dose: 20 mg/m² route of administration: Oral experiment type: SINGLE co-administered:		METHOTREXATE plasma	Homo sapiens population: UNHEALTHY age: CHILD sex: UNKNOWN food status: UNKNOWN

AUC

Value	Dose	Co-administered	Analyte	Population
3533 nM × h EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/8485020	15 mg single, oral dose: 15 mg route of administration: Oral experiment type: SINGLE co-administered:		METHOTREXATE plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED

T_1/2

Value	Dose	Co-administered	Analyte	Population
55 h EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/8485020	15 mg single, oral dose: 15 mg route of administration: Oral experiment type: SINGLE co-administered:		METHOTREXATE plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
3.25 h DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/205776s000lbl.pdf	20 mg/m² single, oral dose: 20 mg/m² route of administration: Oral experiment type: SINGLE co-administered:		METHOTREXATE plasma	Homo sapiens population: UNHEALTHY age: CHILD sex: UNKNOWN food status: UNKNOWN

F_unbound

Value	Dose	Co-administered	Analyte	Population
50% DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/205776s000lbl.pdf			METHOTREXATE serum	Homo sapiens population: UNKNOWN age: UNKNOWN sex: UNKNOWN food status: UNKNOWN

Doses

AEs

Overview

CYP3A4	CYP2C9	CYP2D6	hERG

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
	SLC19A1 4 P-gp 1399 BCRP 506 MRP2 179 OAT1 293 OAT4 70 MRP4 73	SULT1A1 4

Drug as perpetrator

Target	Modality	Activity	Metabolite	Clinical evidence
SULT1A1 8	inducer 1443 Sources: https://pubmed.ncbi.nlm.nih.gov/20668491/ Page: -	yes

Drug as victim

Target	Modality	Activity
OAT4 70	substrate 3107 Sources: https://jpet.aspetjournals.org/content/302/2/666.short Page: -	yes [Km 17.8 uM]
OAT1 293	substrate 3107 Sources: https://jpet.aspetjournals.org/content/302/2/666.short Page: -	yes [Km 553.8 uM]
BCRP 506	substrate 3107 Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5514947/ Page: -	yes
MRP2 179	substrate 3107 Sources: https://journals.lww.com/jpharmacogenetics/Abstract/2005/05000/A_mutation_in_the_drug_transporter_gene_ABCC2.2.aspx Page: -	yes
MRP4 73	substrate 3107 Sources: https://jpet.aspetjournals.org/content/322/3/1162.short Page: -	yes
P-gp 1399	substrate 3107 Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5514947/ Page: -	yes
SLC19A1 4	substrate 3107 Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5514947/ Page: -	yes

Sourcing

Vendor/Aggregator	ID	URL
ChEBI	CHEBI:44185	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:44185
ChemicalBook	CB2704227	https://www.chemicalbook.com/ChemicalProductProperty_EN_CB2704227
ChemicalBook	CB2739302	https://www.chemicalbook.com/ChemicalProductProperty_EN_CB2739302
MolPort	MolPort-003-665-521	https://www.molport.com/shop/molecule-link/MolPort-003-665-521
Selleck Chemicals	Abitrexate	http://www.selleckchem.com/products/Abitrexate.html
ZINC	ZINC000001529323	http://zinc15.docking.org/substances/ZINC000001529323
eMolecules	476359	https://www.emolecules.com/cgi-bin/more?vid=476359

PubMed

Title	Date	PubMed
Cytogenetic studies in a patient with acute granulocytic leukemia of seven and one-half years duration.	1975 Nov	1058041
Letter: Vasculitis as a complication of high-dose methotrexate in the treatment of acute leukemia.	1976 Jun	1065218
Anterior lumbosacral radiculopathy after intrathecal methotrexate treatment.	1999 Aug	10465148
Toxic epidermal necrolysis and graft vs. host disease: a clinical spectrum but a diagnostic dilemma.	1999 Jul	10457124
Intrathecal methotrexate-induced megaloblastic anemia in patients with acute leukemia.	1999 Sep	10458822
Atypical methotrexate dermatitis and vasculitis in a patient with ankylosing spondylitis.	2000	10984137
[A case of rheumatoid arthritis associated with autoimmune hemolytic anemia due to weekly low-dose methotrexate therapy].	2000 Aug	11021173
[Carboxypeptidase-G2-rescue in a woman with methotrexate-induced renal failure].	2000 Aug 15	10985069
Methotrexate, uracil and tegafur, and leucovorin chemotherapy for patients with breast cancer in progression after high-dose chemotherapy with peripheral blood progenitor cell transplant: a phase II study.	2000 Dec	11202810
Atrial fibrillation occurring in a patient taking etanercept plus methotrexate for rheumatoid arthritis.	2000 Dec	11200291
Identification by RNA-based arbitrarily primed PCR of the involvement of cytochrome c oxidase in the development of resistance to methotrexate.	2000 Feb 28	10699469
Veno-occlusive disease of the liver associated with thiopurines in a child with acute lymphoblastic leukemia.	2000 Jul-Aug	10914056
Hepatocellular carcinoma: a rare late event in childhood acute lymphoblastic leukemia.	2000 May-Jun	10864067
Serious liver disease in a patient receiving methotrexate and leflunomide.	2000 Nov	11083289
Expression and characterization of recombinant human-derived Pneumocystis carinii dihydrofolate reductase.	2000 Nov	11036028
Design, synthesis, and X-ray crystal structure of a potent dual inhibitor of thymidylate synthase and dihydrofolate reductase as an antitumor agent.	2000 Oct 19	11052789
Methotrexate treatment protocols and the central nervous system: significant cure with significant neurotoxicity.	2000 Sep	11019787
Cutaneous ulcerations in a patient with rheumatoid arthritis receiving treatment with methotrexate.	2000 Sep	10990260
[Conservative therapy in endocrine orbitopathy: "State of the art"].	2001	11593898
Stereoselectivity of the folate transporter in rabbit small intestine: studies with amethopterin enantiomers.	2001	11270327
Hospital resources used for ectopic pregnancy treatment by laparoscopy and methotrexate.	2001 Apr-Jun	11394423
Transient posterior encephalopathy induced by chemotherapy in children.	2001 Feb	11275465
[Listeria arthritis in chronic polyarthritis during low dose prednisolone and methotrexate therapy. Case report and review of the literature].	2001 Feb	11263013
A comparison of methods of loco-regional chemotherapy combined with systemic chemotherapy as neo-adjuvant treatment of osteosarcoma of the extremity.	2001 Feb	11237499
Neoadjuvant chemotherapy for high grade osteosarcoma of the extremities: long-term results for patients treated according to the Rizzoli IOR/OS-3b protocol.	2001 Feb	11233808
Development of fulminant hepatitis B (precore variant mutant type) after the discontinuation of low-dose methotrexate therapy in a rheumatoid arthritis patient.	2001 Feb	11229464
The value of amino-terminal propeptide of type III procollagen in routine screening for methotrexate-induced liver fibrosis: a 10-year follow-up.	2001 Jan	11167689
A clinical study to determine the efficacy and safety of 1% methotrexate/Azone (MAZ) gel applied topically once daily in patients with psoriasis vulgaris.	2001 Jul	11679005
[Methotrexate, liver and rheumatoid arthritis in tropical areas].	2001 Jul-Sep	11641084
Successful rescue with leucovorin and thymidine in a patient with high-dose methotrexate induced acute renal failure.	2001 Jun	11459208
Motor nervous pathway function is impaired after treatment of childhood acute lymphoblastic leukemia: a study with motor evoked potentials.	2001 Mar	11241435
Inappropriate medical management of spinal epidural abscess.	2001 Mar	11171681
Identification and characterization of human organic anion transporter 3 expressing predominantly in the kidney.	2001 May	11306713
[Meningeal carcinomatosis as the first manifestation of gastric adenocarcinoma].	2001 Oct 11	11787214
Methylation-dependent silencing of the reduced folate carrier gene in inherently methotrexate-resistant human breast cancer cells.	2001 Oct 26	11509559
Isolation of rat dihydrofolate reductase gene and characterization of recombinant enzyme.	2001 Sep	11502523
Neurotoxicity with leukoencephalopathy after a single intravenous high dose of methotrexate in a patient with lymphoma.	2002	11978942
Multiple anomalies in a fetus exposed to low-dose methotrexate in the first trimester.	2002 Apr	12039119
Methotrexate leukoencephalopathy presenting as Klüver-Bucy syndrome and uncinate seizures.	2002 Apr	11992760
Methotrexate-induced systemic vasculitis.	2002 Feb	11813187
High-dose cyclophosphamide followed by autologous peripheral blood progenitor cell transplantation improves the salvage treatment for persistent or sensitive relapsed malignant lymphoma.	2002 Jan	11743614
Isolation, characterization and differential gene expression of multispecific organic anion transporter 2 in mice.	2002 Jul	12065749
CYP3A4 induction by drugs: correlation between a pregnane X receptor reporter gene assay and CYP3A4 expression in human hepatocytes.	2002 Jul	12065438
Oral methotrexate for treatment of ectopic pregnancy.	2002 Jun	12066097
Radiation myelitis in a 5-year-old girl.	2002 Mar	12026238
Nephrotoxicity due to intermediate-dose methotrexate without rescue in an obese adolescent with acute lymphoblastic leukemia.	2002 Mar	11881788
The MRP4/ABCC4 gene encodes a novel apical organic anion transporter in human kidney proximal tubules: putative efflux pump for urinary cAMP and cGMP.	2002 Mar	11856762
Quantitative MRI assessment of leukoencephalopathy.	2002 May	11979570
CNS late-effects after ALL therapy in childhood. Part III: neuropsychological performance in long-term survivors of childhood ALL: impairments of concentration, attention, and memory.	2002 May	11979456
Comparison of abortions induced by methotrexate or mifepristone followed by misoprostol.	2002 May	11978292

Patents

Sample Use Guides

In Vivo Use Guide

Usual Adult Dose for Acute Lymphoblastic Leukemia Induction: 3.3 mg/m2/day orally or IM (in combination with prednisone 60 mg/m2) daily Usual Adult Dose for Psoriasis Single Dose: 7.5 mg/week orally, IM, or IV until adequate response is achieved Divided Dose: 2.5 mg orally, IM, or IV every 12 hours for 3 doses once a week Maximum weekly dose: 20 mg

Route of Administration: Other

In Vitro Use Guide

VEGF and Ang-1 levels were significantly lower, and Ang-2 levels were significantly higher in NPs (organ-cultured nasal polyps) treated with 100-umolar Methotrexate than in nontreated NPs

Substance Class	Chemical Created by `admin` on `Sat Jun 26 14:29:47 UTC 2021` Edited by `admin` on `Sat Jun 26 14:29:47 UTC 2021`
Record UNII	3IG1E710ZN
Record Status	`Validated (UNII)`
Record Version

Download

Name

Type

Language

METHOTREXATE SODIUM

Common Name

English

ABITREXATE

Brand Name

English

METHOTREXATE SODIUM SALT

Common Name

English

METHOTREXATE (AS DISODIUM)

Common Name

English

METHOTREXATE SODIUM [VANDF]

Common Name

English

MEXATE

Brand Name

English

TREXALL

Brand Name

English

ADX-2191 SODIUM

Code

English

METHOTREXATE SODIUM [WHO-DD]

Common Name

English

METHOTREXATE DISODIUM

Common Name

English

SODIUM L-(+)-METHOTREXATE

Common Name

English

FOLEX

Brand Name

English

DISODIUM METHOTREXATE

Common Name

English

METHOTREXATE SODIUM [ORANGE BOOK]

Common Name

English

METHOTREXATE DISODIUM SALT [MI]

Common Name

English

METHOTREXATE DISODIUM SALT

Common Name

English

METHOTREXATE SODIUM [MART.]

Common Name

English

METHOTREXATE, SODIUM SALT

Common Name

English

Classification Tree Code System Code

NCI_THESAURUS

C2153