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=CN=C2N=C(N)N=C(N)C2=N1)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

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 57 Target ID: CHEMBL202 Sources: http://www.drugbank.ca/drugs/DB00563	Inhibitor 8297	5.19 pM [Ki]
Serum paraoxonase/arylesterase 1 31 Target ID: CHEMBL3167 Sources: https://www.ncbi.nlm.nih.gov/pubmed/26458405	Inhibitor 8297	0.18 mM [IC50]
HT-1080 4 Target ID: CHEMBL614580 Sources: https://www.ncbi.nlm.nih.gov/pubmed/11555609	Inhibitor 8297	15.0 nM [IC50]

Conditions

Condition	Modality	Highest Phase	Product
Rheumatoid arthritis 316 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/204824s004lbl.pdf	Primary	Approved 8429	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 8429	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 434 Sources: https://www.drugs.com/pro/methotrexate-injection.html	Primary	Approved 8429	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 69 Sources: https://www.drugs.com/pro/methotrexate-injection.html	Primary	Approved 8429	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
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 1537 BCRP 561 MRP2 205 OAT1 326 OAT4 78 MRP4 77	SULT1A1 4

Drug as perpetrator

Target	Modality	Activity	Metabolite	Clinical evidence
SULT1A1 8	inducer 1573 Sources: https://pubmed.ncbi.nlm.nih.gov/20668491/ Page: -	yes

Drug as victim

Target	Modality	Activity
OAT4 78	substrate 3367 Sources: https://jpet.aspetjournals.org/content/302/2/666.short Page: -	yes [Km 17.8 uM]
OAT1 326	substrate 3367 Sources: https://jpet.aspetjournals.org/content/302/2/666.short Page: -	yes [Km 553.8 uM]
BCRP 561	substrate 3367 Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5514947/ Page: -	yes
MRP2 205	substrate 3367 Sources: https://journals.lww.com/jpharmacogenetics/Abstract/2005/05000/A_mutation_in_the_drug_transporter_gene_ABCC2.2.aspx Page: -	yes
MRP4 77	substrate 3367 Sources: https://jpet.aspetjournals.org/content/322/3/1162.short Page: -	yes
P-gp 1537	substrate 3367 Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5514947/ Page: -	yes
SLC19A1 4	substrate 3367 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
[Disseminated necrotizing leukoencephalopathy following intrathecal methotrexate in childhood leukemia (author's transl)].	1976 Jan	1062350
Letter: Vasculitis as a complication of high-dose methotrexate in the treatment of acute leukemia.	1976 Jun	1065218
Combination therapy in early rheumatoid arthritis: a randomised, controlled, double blind 52 week clinical trial of sulphasalazine and methotrexate compared with the single components.	1999 Apr	10364900
Management of separation pain after single-dose methotrexate therapy for ectopic pregnancy.	1999 Apr	10214839
Leukoencephalopathy complicating an Ommaya reservoir and chemotherapy.	1999 Feb	10090607
Prospective evaluation of high-dose ifosfamide-related nephrotoxicity in young adult patients with recurrent osteosarcoma previously treated with cisplatin, methotrexate and standard-dose ifosfamide.	1999 Jan	10194544
Delayed methotrexate clearance in a patient with sickle cell anemia and osteosarcoma.	1999 Mar-Apr	10206466
Angio-neurotic oedema associated with methotrexate treatment in rheumatoid arthritis.	1999 Sep	10515658
Atrial fibrillation occurring in a patient taking etanercept plus methotrexate for rheumatoid arthritis.	2000 Dec	11200291
Acute stroke-like encephalopathy associated with high-dose methotrexate impurities.	2000 Jul-Aug	10959910
Cortical laminar necrosis caused by immunosuppressive therapy and chemotherapy.	2000 Mar	10730638
Hepatocellular carcinoma: a rare late event in childhood acute lymphoblastic leukemia.	2000 May-Jun	10864067
Acute neurotoxicity in children with B-lineage acute lymphoblastic leukemia (B-ALL) treated with intermediate risk protocols.	2000 Nov	11070476
Stereoselectivity of the folate transporter in rabbit small intestine: studies with amethopterin enantiomers.	2001	11270327
A comparison of methods of loco-regional chemotherapy combined with systemic chemotherapy as neo-adjuvant treatment of osteosarcoma of the extremity.	2001 Feb	11237499
Relationship between dose-intensity of treatment and outcome for patients with osteosarcoma of the extremity treated with neoadjuvant chemotherapy.	2001 Jul-Aug	11410803
[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
Homocysteine modulation as a reason for continuous folic acid supplementation in methotrexate-treated rheumatoid arthritis patients.	2001 Jun	11426040
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
Tamoxifen-based treatment induces clinically meaningful responses in multiple myeloma patients with relapsing disease after autotransplantation.	2001 Nov-Dec	11911415
Methylation-dependent silencing of the reduced folate carrier gene in inherently methotrexate-resistant human breast cancer cells.	2001 Oct 26	11509559
Multiple anomalies in a fetus exposed to low-dose methotrexate in the first trimester.	2002 Apr	12039119
CYP3A4 induction by drugs: correlation between a pregnane X receptor reporter gene assay and CYP3A4 expression in human hepatocytes.	2002 Jul	12065438
Radiation myelitis in a 5-year-old girl.	2002 Mar	12026238
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

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

Name

Type

Language

METHOTREXATE MONOHYDRATE

Common Name

English

METHOTREXATE MONOHYDRATE [MI]

Common Name

English

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

Common Name

English

Code System Code Type Description

CAS

6745-93-3