METHOTREXATE MONOHYDRATE

First approved in 1953

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C20H22N8O5.H2O
Molecular Weight	472.4546
Optical Activity	UNSPECIFIED
Defined Stereocenters	1 / 1
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

O.CN(CC1=NC2=C(N)N=C(N)N=C2N=C1)C3=CC=C(C=C3)C(=O)N[C@@H](CCC(O)=O)C(O)=O

InChI

InChIKey=FPJYMUQSRFJSEW-ZOWNYOTGSA-N

InChI=1S/C20H22N8O5.H2O/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);1H2/t13-;/m0./s1

HIDE SMILES / InChI

Molecular Formula	H2O
Molecular Weight	18.0153
Charge	0
Count

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

Molecular Formula	C20H22N8O5
Molecular Weight	454.4393
Charge	0
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 61 Target ID: CHEMBL202 Sources: http://www.drugbank.ca/drugs/DB00563	Inhibitor 8504	5.19 pM [Ki]
Serum paraoxonase/arylesterase 1 31 Target ID: CHEMBL3167 Sources: https://www.ncbi.nlm.nih.gov/pubmed/26458405	Inhibitor 8504	0.18 mM [IC50]
HT-1080 4 Target ID: CHEMBL614580 Sources: https://www.ncbi.nlm.nih.gov/pubmed/11555609	Inhibitor 8504	15.0 nM [IC50]

Conditions

Condition	Modality	Highest Phase	Product
Rheumatoid arthritis 320 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/204824s004lbl.pdf	Primary	Approved 8583	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 1952
Gestational choriocarcinoma 4 Sources: https://www.drugs.com/pro/methotrexate-injection.html	Primary	Approved 8583	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 2001
Breast cancer 432 Sources: https://www.drugs.com/pro/methotrexate-injection.html	Primary	Approved 8583	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 2001
Lung cancer 70 Sources: https://www.drugs.com/pro/methotrexate-injection.html	Primary	Approved 8583	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 2001

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
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
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

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 6 P-gp 2052 BCRP 697 MRP2 252 OAT1 395 OAT4 93 MRP4 91	SULT1A1 4

Drug as perpetrator

Target	Modality	Activity	Metabolite	Clinical evidence
SULT1A1 8	inducer 1966 Sources: https://pubmed.ncbi.nlm.nih.gov/20668491/ Page: -	yes

Drug as victim

Target	Modality	Activity
OAT4 93	substrate 4014 Sources: https://jpet.aspetjournals.org/content/302/2/666.short Page: -	yes [Km 17.8 uM]
OAT1 395	substrate 4014 Sources: https://jpet.aspetjournals.org/content/302/2/666.short Page: -	yes [Km 553.8 uM]
BCRP 697	substrate 4014 Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5514947/ Page: -	yes
MRP2 252	substrate 4014 Sources: https://journals.lww.com/jpharmacogenetics/Abstract/2005/05000/A_mutation_in_the_drug_transporter_gene_ABCC2.2.aspx Page: -	yes
MRP4 91	substrate 4014 Sources: https://jpet.aspetjournals.org/content/322/3/1162.short Page: -	yes
P-gp 2052	substrate 4014 Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5514947/ Page: -	yes
SLC19A1 6	substrate 4014 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
eMolecules	476359	https://www.emolecules.com/cgi-bin/more?vid=476359
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

PubMed

Title	Date	PubMed
Isolation, characterization and differential gene expression of multispecific organic anion transporter 2 in mice.	2002-07	12065749
CYP3A4 induction by drugs: correlation between a pregnane X receptor reporter gene assay and CYP3A4 expression in human hepatocytes.	2002-07	12065438
Oral methotrexate for treatment of ectopic pregnancy.	2002-06	12066097
Quantitative MRI assessment of leukoencephalopathy.	2002-05	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.	2002-05	11979456
Comparison of abortions induced by methotrexate or mifepristone followed by misoprostol.	2002-05	11978292
Multiple anomalies in a fetus exposed to low-dose methotrexate in the first trimester.	2002-04	12039119
Methotrexate leukoencephalopathy presenting as Klüver-Bucy syndrome and uncinate seizures.	2002-04	11992760
Tamoxifen-based treatment induces clinically meaningful responses in multiple myeloma patients with relapsing disease after autotransplantation.	2002-03-26	11911415
Radiation myelitis in a 5-year-old girl.	2002-03	12026238
CT and MRI appearances of methotrexate leucoencephalopathy.	2002-03	11966594
[A case of subacute transient cerebral dysfunction in a osteosarcoma patient following high-dose methotrexate].	2002-03	11915742
Nephrotoxicity due to intermediate-dose methotrexate without rescue in an obese adolescent with acute lymphoblastic leukemia.	2002-03	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.	2002-03	11856762
Methotrexate-induced nephrogenic diabetes insipidus: first case report.	2002-02	11886979
Methotrexate-induced systemic vasculitis.	2002-02	11813187
Leukemic leptomeningeal involvement in stage 0 and stage 1 chronic lymphocytic leukemia.	2002-01	11908730
Methotrexate-related nonnecrotizing multifocal axonopathy detected by beta-amyloid precursor protein immunohistochemistry.	2002-01	11800653
High-dose cyclophosphamide followed by autologous peripheral blood progenitor cell transplantation improves the salvage treatment for persistent or sensitive relapsed malignant lymphoma.	2002-01	11743614
Neurotoxicity with leukoencephalopathy after a single intravenous high dose of methotrexate in a patient with lymphoma.	2002	11978942
Randomized, double-blind, crossover, placebo-controlled trial of intravenous ondansetron for the prevention of intrathecal chemotherapy-induced vomiting in children.	2001-12	11902300
Role of non-alcoholic steatohepatitis in methotrexate-induced liver injury.	2001-12	11851839
Neoadjuvant chemotherapy for osteosarcoma of the extremity: long-term results of the Rizzoli's 4th protocol.	2001-11	11597381
Methylation-dependent silencing of the reduced folate carrier gene in inherently methotrexate-resistant human breast cancer cells.	2001-10-26	11509559
[Methotrexate, liver and rheumatoid arthritis in tropical areas].	2001-10-20	11641084
Mutation of Trp1254 in the multispecific organic anion transporter, multidrug resistance protein 2 (MRP2) (ABCC2), alters substrate specificity and results in loss of methotrexate transport activity.	2001-10-12	11500505
[Meningeal carcinomatosis as the first manifestation of gastric adenocarcinoma].	2001-10-11	11787214
Isolation of rat dihydrofolate reductase gene and characterization of recombinant enzyme.	2001-09	11502523
Long-term cerebral metabolite changes on proton magnetic resonance spectroscopy in patients cured of acute lymphoblastic leukemia with previous intrathecal methotrexate and cranial irradiation prophylaxis.	2001-07-01	11395245
A clinical study to determine the efficacy and safety of 1% methotrexate/Azone (MAZ) gel applied topically once daily in patients with psoriasis vulgaris.	2001-07	11679005
[Fatal outcome of a multisystemic sarcoidosis in a 54-year-old patient].	2001-07	11481582
Relationship between dose-intensity of treatment and outcome for patients with osteosarcoma of the extremity treated with neoadjuvant chemotherapy.	2001-06-19	11410803
Hospital resources used for ectopic pregnancy treatment by laparoscopy and methotrexate.	2001-06-08	11394423
Successful rescue with leucovorin and thymidine in a patient with high-dose methotrexate induced acute renal failure.	2001-06	11459208
Homocysteine modulation as a reason for continuous folic acid supplementation in methotrexate-treated rheumatoid arthritis patients.	2001-06	11426040
Identification and characterization of human organic anion transporter 3 expressing predominantly in the kidney.	2001-05	11306713
Motor nervous pathway function is impaired after treatment of childhood acute lymphoblastic leukemia: a study with motor evoked potentials.	2001-03	11241435
Inappropriate medical management of spinal epidural abscess.	2001-03	11171681
Transient posterior encephalopathy induced by chemotherapy in children.	2001-02	11275465
[Listeria arthritis in chronic polyarthritis during low dose prednisolone and methotrexate therapy. Case report and review of the literature].	2001-02	11263013
A comparison of methods of loco-regional chemotherapy combined with systemic chemotherapy as neo-adjuvant treatment of osteosarcoma of the extremity.	2001-02	11237499
Neoadjuvant chemotherapy for high grade osteosarcoma of the extremities: long-term results for patients treated according to the Rizzoli IOR/OS-3b protocol.	2001-02	11233808
Development of fulminant hepatitis B (precore variant mutant type) after the discontinuation of low-dose methotrexate therapy in a rheumatoid arthritis patient.	2001-02	11229464
The value of amino-terminal propeptide of type III procollagen in routine screening for methotrexate-induced liver fibrosis: a 10-year follow-up.	2001-01	11167689
Toxicity of methotrexate treatment in psoriasis and psoriatic arthritis--short- and long-term toxicity in 104 patients.	2001	11771523
[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
Adjuvant doxorubicin and cyclophosphamide versus cyclophosphamide, methotrexate, and 5-fluorouracil chemotherapy in premenopausal women with axillary lymph node positive breast carcinoma.	2000-12-15	11135211
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.	2000-12	11202810
Atrial fibrillation occurring in a patient taking etanercept plus methotrexate for rheumatoid arthritis.	2000-12	11200291

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 `Tue Apr 01 16:22:54 GMT 2025` Edited by `admin` on `Tue Apr 01 16:22:54 GMT 2025`
Record UNII	84DMZ3IHO0
Record Status	`Validated (UNII)`
Record Version

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Name

Type

Language

L-GLUTAMIC ACID, N-(4-(((2,4-DIAMINO-6-PTERIDINYL)METHYL)METHYLAMINO)BENZOYL)-, HYDRATE (1:1)

Preferred Name

English

METHOTREXATE MONOHYDRATE

Common Name

English

METHOTREXATE MONOHYDRATE [MI]

Common Name

English

Code System Code Type Description

CAS

6745-93-3