METHOTREXATE

First approved in 1953

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C20H22N8O5
Molecular Weight	454.4393
Optical Activity	UNSPECIFIED
Defined Stereocenters	1 / 1
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

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=FBOZXECLQNJBKD-ZDUSSCGKSA-N

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

HIDE SMILES / InChI

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 56 Target ID: CHEMBL202 Sources: http://www.drugbank.ca/drugs/DB00563	Inhibitor 8228	5.19 pM [Ki]
Serum paraoxonase/arylesterase 1 31 Target ID: CHEMBL3167 Sources: https://www.ncbi.nlm.nih.gov/pubmed/26458405	Inhibitor 8228	0.18 mM [IC50]
HT-1080 4 Target ID: CHEMBL614580 Sources: https://www.ncbi.nlm.nih.gov/pubmed/11555609	Inhibitor 8228	15.0 nM [IC50]

Conditions

Condition	Modality	Highest Phase	Product
Rheumatoid arthritis 313 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/204824s004lbl.pdf	Primary	Approved 8360	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 8360	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 431 Sources: https://www.drugs.com/pro/methotrexate-injection.html	Primary	Approved 8360	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 69 Sources: https://www.drugs.com/pro/methotrexate-injection.html	Primary	Approved 8360	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 1527 BCRP 555 MRP2 201 OAT1 320 OAT4 76 MRP4 75	SULT1A1 4

Drug as perpetrator

Target	Modality	Activity	Metabolite	Clinical evidence
SULT1A1 8	inducer 1542 Sources: https://pubmed.ncbi.nlm.nih.gov/20668491/ Page: -	yes

Drug as victim

Target	Modality	Activity
OAT4 76	substrate 3326 Sources: https://jpet.aspetjournals.org/content/302/2/666.short Page: -	yes [Km 17.8 uM]
OAT1 320	substrate 3326 Sources: https://jpet.aspetjournals.org/content/302/2/666.short Page: -	yes [Km 553.8 uM]
BCRP 555	substrate 3326 Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5514947/ Page: -	yes
MRP2 201	substrate 3326 Sources: https://journals.lww.com/jpharmacogenetics/Abstract/2005/05000/A_mutation_in_the_drug_transporter_gene_ABCC2.2.aspx Page: -	yes
MRP4 75	substrate 3326 Sources: https://jpet.aspetjournals.org/content/322/3/1162.short Page: -	yes
P-gp 1527	substrate 3326 Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5514947/ Page: -	yes
SLC19A1 4	substrate 3326 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
Intracerebral calcifications appearing during the course of acute lymphocytic leukemia treated with methotrexate and X-rays.	1975 Feb	1053935
Cytogenetic studies in a patient with acute granulocytic leukemia of seven and one-half years duration.	1975 Nov	1058041
Cerebral calcifications associated with intrathecal methotrexate therapy in acute lymphocytic leukemia.	1976 Apr	1062546
Letter: Vasculitis as a complication of high-dose methotrexate in the treatment of acute leukemia.	1976 Jun	1065218
[Methotrexate pneumonitis arising during the treatment of non-Hodgkin's lymphomas with the m-BACOD protocol].	1995 Jan	10846532
Toxicity profile of methotrexate in rheumatoid arthritis. A preliminary survey.	1999	10599370
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
Inhibitory effects of combinations of HER-2/neu antibody and chemotherapeutic agents used for treatment of human breast cancers.	1999 Apr 1	10327070
Acute dysarthria induced by low dose methotrexate therapy in a patient with erythrodermic cutaneous T-cell lymphoma: an unusual manifestation of neurotoxicity.	1999 Jan	10233644
Delayed methotrexate clearance in a patient with sickle cell anemia and osteosarcoma.	1999 Mar-Apr	10206466
Porphyria cutanea tarda affecting a rheumatoid arthritis patient treated with methotrexate: association or coincidence?	1999 May	10371285
Low-dose oral pulse methotrexate as monotherapy in elderly patients with bullous pemphigoid.	1999 May	10321603
Carboxypeptidase G2 rescue in a 79 year-old patient with cranial lymphoma after high-dose methotrexate induced acute renal failure.	1999 Nov	10609804
Serosal complications of single-agent low-dose methotrexate used in gestational trophoblastic diseases: first reported case of methotrexate-induced peritonitis.	1999 Nov	10576662
Antifungal activities of antineoplastic agents: Saccharomyces cerevisiae as a model system to study drug action.	1999 Oct	10515904
Atypical methotrexate dermatitis and vasculitis in a patient with ankylosing spondylitis.	2000	10984137
Influence of cyclosporin A on radiological progression in early rheumatoid arthritis patients: a 42-month prospective study.	2000	10776690
[A case of rheumatoid arthritis associated with autoimmune hemolytic anemia due to weekly low-dose methotrexate therapy].	2000 Aug	11021173
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
Manic episode in an ifosfamide-treated patient.	2000 Jan-Feb	10766557
Impotence in a patient with rheumatoid arthritis treated with methotrexate.	2000 Jul	10914881
Cerebral vasculopathy and multiple infarctions in a woman with carcinomatous meningitis while on treatment with intrathecal methotrexate.	2000 May	11026695
Hepatocellular carcinoma: a rare late event in childhood acute lymphoblastic leukemia.	2000 May-Jun	10864067
Expression and characterization of recombinant human-derived Pneumocystis carinii dihydrofolate reductase.	2000 Nov	11036028
Methotrexate treatment protocols and the central nervous system: significant cure with significant neurotoxicity.	2000 Sep	11019787
Treatment for primary CNS lymphoma: the next step.	2000 Sep	10963643
Randomized, double-blind, crossover, placebo-controlled trial of intravenous ondansetron for the prevention of intrathecal chemotherapy-induced vomiting in children.	2001 Dec	11902300
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
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
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 Oct 12	11500505
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
CT and MRI appearances of methotrexate leucoencephalopathy.	2002 Mar	11966594
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

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 `Wed Jul 05 22:52:02 UTC 2023` Edited by `admin` on `Wed Jul 05 22:52:02 UTC 2023`
Record UNII	YL5FZ2Y5U1
Record Status	`Validated (UNII)`
Record Version

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Name

Type

Language

METHOTREXATE

Official Name

English

METHOTREXATE [WHO-IP]

Common Name

English

METHOTREXATE [USP-RS]

Common Name

English

METHYLAMINOPTERIN

Common Name

English

METHOTREXATE [EP MONOGRAPH]

Common Name

English

Methotrexate [WHO-DD]

Common Name

English

methotrexate [INN]

Common Name

English

METHOTREXATUM [WHO-IP LATIN]

Common Name

English

METHOTREXATE [IARC]

Common Name

English

METHOTREXATE [USAN]

Common Name

English

METHOTREXATE [ORANGE BOOK]

Common Name

English

AMETHOPTERIN

Common Name

English

XATMEP

Brand Name

English

METHOTREXATE [MART.]

Common Name

English

ADX-2191

Code

English

METHOTREXATE [MI]

Common Name

English

REDITREX

Brand Name

English

R-9985

Code

English

CL-14377

Code

English

METHOTREXATE [USP MONOGRAPH]

Common Name

English

METHOTREXATE [INCI]

Common Name

English

METHOTREXATE [HSDB]

Common Name

English

MTX

Common Name

English

RASUVO

Brand Name

English

METHOTREXATE [USP IMPURITY]

Common Name

English

CL 14377

Code

English

NSC-740

Code

English

METHOTREXATE [JAN]

Common Name

English

(2S)-2-((4-(((2,4-DIAMINOPTERIDIN-6-YL)METHYL)(METHYL)AMINO)BENZOYL)AMINO)PENTANEDIOIC ACID

Systematic Name

English

METHOTREXATE [VANDF]

Common Name

English

JYLAMVO

Brand Name

English

Classification Tree Code System Code

IARC

Methotrexate

FDA ORPHAN DRUG

469315