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Identification
NameMethotrexate
Accession NumberDB00563  (APRD00353)
TypeSmall Molecule
GroupsApproved
Description

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]

Structure
Thumb
Synonyms
4-amino-10-methylfolic acid
4-amino-N(10)-Methylpteroylglutamic acid
Amethopterin
Emtexate
Ledertrexate
Methotrexat
Méthotrexate
Methotrexatum
Metotrexato
MTX
N-[4-[[(2,4-Diamino-6-pteridinyl)methyl]methylamino]benzoyl]-L-glutamic acid
Rheumatrex
Trexall
External Identifiers Not Available
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Jamp-methotrexatesolution25 mgintra-arterial; intramuscular; intrathecal; intravenousJamp Pharma Corporation2014-03-12Not applicableCanada
Methotrexatetablet2.5 mg/1oralMajor Pharmaceuticals2009-06-012016-04-05Us
Methotrexatesolution25 mgintra-arterial; intramuscular; intravenousPfizer Canada Inc1997-01-242011-05-03Canada
Methotrexatetablet2.5 mg/1oralPd Rx Pharmaceuticals, Inc.1953-12-072016-04-05Us
Methotrexatetablet2.5 mg/1oralA S Medication Solutions1953-12-072016-04-01Us
Methotrexatetablet2.5 mg/1oralDAVA Pharmaceuticals, Inc.1953-12-072016-04-05Us
Methotrexatetablet2.5 mg/1oralDispensing Solutions, Inc.1953-12-072016-04-05Us
Methotrexatetablet2.5 mgoralPfizer Canada Inc1996-11-15Not applicableCanada
Methotrexatetablet2.5 mg/1oralREMEDYREPACK INC.2015-09-232016-04-05Us
Methotrexateinjection, solution25 mg/mLintra-arterial; intramuscular; intrathecal; intravenousHospira Worldwide, Inc.1959-08-102016-04-05Us
Methotrexateinjection, solution25 mg/mLintra-arterial; intramuscular; intravenousHospira Worldwide, Inc.1959-08-102016-04-05Us
Methotrexatetablet2.5 mg/1oralRebel Distributors Corp1953-12-072016-04-05Us
Methotrexate Dbl Inj 10mg/mlliquid10 mgintravenousDavid Bull Laboratories (Pty) Ltd.1985-12-311997-08-14Canada
Methotrexate Dbl Inj 2.5mg/mlliquid2.5 mgintravenousDavid Bull Laboratories (Pty) Ltd.1985-12-311998-08-13Canada
Methotrexate Dbl Inj 25mg/mlliquid25 mgintravenousDavid Bull Laboratories (Pty) Ltd.1985-12-311998-08-13Canada
Methotrexate Injection BPsolution25 mgintra-arterial; intramuscular; intrathecal; intravenousUman Pharma IncNot applicableNot applicableCanada
Methotrexate Injection USPsolution25 mgintra-arterial; intramuscular; intravenousSandoz Canada Incorporated2013-02-14Not applicableCanada
Methotrexate Injection, BPsolution25 mgintra-arterial; intramuscular; intrathecal; intravenousPharmascience Inc2014-05-08Not applicableCanada
Methotrexate Injection, BPsolution25 mgintra-arterial; intramuscular; intrathecal; intravenousAccord Healthcare Inc2011-09-30Not applicableCanada
Methotrexate Injection, BPsolution20 mgintra-arterial; intramuscular; intrathecal; intravenousPharmascience Inc2014-05-08Not applicableCanada
Methotrexate Injection, BPsolution15 mgintra-arterial; intramuscular; intrathecal; intravenousPharmascience Inc2014-05-08Not applicableCanada
Methotrexate Injection, BPsolution10 mgintra-arterial; intramuscular; intrathecal; intravenousPharmascience Inc2014-05-08Not applicableCanada
Methotrexate Injection, BPsolution7.5 mgintra-arterial; intramuscular; intrathecal; intravenousPharmascience Inc2014-05-08Not applicableCanada
Methotrexate Injection, USPsolution25 mgintra-arterial; intramuscular; intrathecal; intravenousMylan Pharmaceuticals Ulc2014-08-14Not applicableCanada
Methotrexate Injection, USPsolution25 mgintravenousHospira Healthcare Corporation1997-07-30Not applicableCanada
Methotrexate Injection, USPsolution25 mgintra-arterial; intramuscular; intrathecal; intravenousHospira Healthcare Corporation1998-07-13Not applicableCanada
Methotrexate Injection, USPsolution10 mgintra-arterial; intramuscular; intrathecal; intravenousHospira Healthcare Corporation1997-07-30Not applicableCanada
Methotrexate Injection, USPsolution25 mgintra-arterial; intramuscular; intravenousHospira Healthcare Corporation1998-04-30Not applicableCanada
Methotrexate PF/sa Injectionsolution25 mgintra-arterial; intramuscular; intrathecal; intravenousSandoz Canada IncorporatedNot applicableNot applicableCanada
Methotrexate Sod Inj 25mg/ml USPliquid25 mgintra-arterial; intramuscular; intrathecal; intravenousDavid Bull Laboratories (Pty) Ltd.1990-12-311998-08-13Canada
Methotrexate Sodiumtablet2.5 mg/1oralGen Pak Solutions Llc2012-10-012016-04-05Us
Methotrexate Sodium Inj 20mgpowder for solution20 mgintramuscular; intrathecal; intravenousLederle Cyanamid Canada Inc.1977-12-311997-08-14Canada
Methotrexate Sodium Inj 25.0mg/mlliquid25 mgintramuscular; intrathecal; intravenousLederle Cyanamid Canada Inc.1976-12-311997-08-14Canada
Methotrexate Sodium Inj 25mg/mlliquid50 mgintramuscular; intrathecal; intravenousLederle Cyanamid Canada Inc.1981-12-311997-08-14Canada
Methotrexate Sodium Inj 25mg/ml USPliquid25 mgintra-arterial; intramuscular; intrathecal; intravenousDavid Bull Laboratories (Pty) Ltd.1992-12-311999-08-10Canada
Methotrexate Sodium Injectionsolution25 mgintra-arterial; intramuscular; intrathecal; intravenousTeva Canada Limited1995-12-31Not applicableCanada
Methotrexate Sodium Injection USPsolution25 mgintra-arterial; intramuscular; intrathecal; intravenous; intraventricularPfizer Canada Inc1996-09-052006-08-02Canada
Methotrexate Tab 2.5mgtablet2.5 mgoralLederle Cyanamid Canada Inc.1955-12-311997-08-14Canada
Methotrexate Tab 2.5mg USPtablet2.5 mgoralDavid Bull Laboratories (Pty) Ltd.1991-12-312000-08-01Canada
Methotrexate Tablets, USPtablet10 mgoralHospira Healthcare Corporation2004-04-12Not applicableCanada
Methotrexate-liq Im IV Iar Int Ivr 25mg/mlliquid25 mgintra-arterial; intramuscular; intrathecal; intravenousWyeth Ayerst Canada Inc.1997-02-042001-09-19Canada
Methotrexate-pws Im IV Iar Int Ivr 20mg/vialpowder for solution20 mgintra-arterial; intramuscular; intrathecal; intravenousWyeth Ayerst Canada Inc.1997-02-042001-05-22Canada
Metojectsolution20 mgintra-arterial; intramuscular; intravenousMedexus Inc2008-05-30Not applicableCanada
Metojectsolution7.5 mgintra-arterial; intramuscular; intravenousMedexus Inc2009-01-26Not applicableCanada
Metojectsolution25 mgintra-arterial; intramuscular; intravenousMedexus Inc2009-01-26Not applicableCanada
Metojectsolution15 mgintra-arterial; intramuscular; intravenousMedexus Inc2009-01-26Not applicableCanada
Metojectsolution10 mgintra-arterial; intramuscular; intravenousMedexus Inc2009-01-26Not applicableCanada
Otrexupinjection, solution7.5 mg/.4mLsubcutaneousAntares Pharma, Inc.2013-10-112016-04-05Us
Otrexupinjection, solution25 mg/.4mLsubcutaneousAntares Pharma, Inc.2013-10-112016-04-05Us
Otrexupinjection, solution20 mg/.4mLsubcutaneousAntares Pharma, Inc.2013-10-112016-04-05Us
Otrexupinjection, solution15 mg/.4mLsubcutaneousAntares Pharma, Inc.2013-10-112016-04-05Us
Otrexupinjection, solution10 mg/.4mLsubcutaneousAntares Pharma, Inc.2013-10-112016-04-05Us
Rasuvoinjection, solution27.5 mg/.55mLsubcutaneousMedac Pharma, Inc2014-07-102016-04-05Us
Rasuvoinjection, solution30 mg/.6mLsubcutaneousMedac Pharma, Inc2014-07-102016-04-05Us
Rasuvoinjection, solution7.5 mg/.15mLsubcutaneousMedac Pharma, Inc2014-07-102016-04-05Us
Rasuvoinjection, solution25 mg/.5mLsubcutaneousMedac Pharma, Inc2014-07-102016-04-05Us
Rasuvoinjection, solution22.5 mg/.45mLsubcutaneousMedac Pharma, Inc2014-07-102016-04-05Us
Rasuvoinjection, solution20 mg/.4mLsubcutaneousMedac Pharma, Inc2014-07-102016-04-05Us
Rasuvoinjection, solution17.5 mg/.35mLsubcutaneousMedac Pharma, Inc2014-07-102016-04-05Us
Rasuvoinjection, solution15 mg/.3mLsubcutaneousMedac Pharma, Inc2014-07-102016-04-05Us
Rasuvoinjection, solution12.5 mg/.25mLsubcutaneousMedac Pharma, Inc2014-07-102016-04-05Us
Rasuvoinjection, solution10 mg/.2mLsubcutaneousMedac Pharma, Inc2014-07-102016-04-05Us
Ratio-methotrexate Sodiumtablet2.5 mgoralTeva Canada Limited2001-11-14Not applicableCanada
Rheumatrex Dose Packtablet2.5 mg/1oralDAVA Pharmaceuticals, Inc.1953-07-122016-04-05Us
Rheumatrex Tab 2.5mgtablet2.5 mgoralLederle Cyanamid Canada Inc.1990-12-312000-08-02Canada
Rheumatrex-tab 2.5mgtablet2.5 mgoralWyeth Ayerst Canada Inc.1999-04-122000-08-02Canada
Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Apo-methotrexatetablet2.5 mgoralApotex IncNot applicableNot applicableCanada
Apo-methotrexatetablet2.5 mgoralHospira Healthcare Corporation1999-09-17Not applicableCanada
Methotrexateinjection25 mg/mLintra-arterial; intramuscular; intrathecal; intravenousMylan Institutional LLC2012-03-302016-04-05Us
Methotrexateinjection, powder, lyophilized, for solution1 g/1intra-arterial; intramuscular; intrathecal; intravenousFresenius Kabi USA, LLC2000-01-222016-04-05Us
Methotrexatetablet2.5 mg/1oralMylan Institutional Inc.1995-07-132016-04-05Us
Methotrexatetablet2.5 mg/1oralMylan Pharmaceuticals Inc.1992-05-182016-04-23Us
Methotrexateinjection25 mg/mLintra-arterial; intramuscular; intrathecal; intravenousMylan Institutional LLC2012-03-302016-04-05Us
Methotrexateinjection25 mg/mLintra-arterial; intramuscular; intrathecal; intravenousMylan Institutional LLC2012-03-302016-04-05Us
Methotrexateinjection, solution25 mg/mLintra-arterial; intramuscular; intrathecal; intravenousFresenius Kabi USA, LLC2003-04-032016-04-05Us
Methotrexateinjection, solution25 mg/mLintra-arterial; intramuscular; intrathecal; intravenousTeva Parenteral Medicines, Inc.2012-08-012016-04-05Us
Methotrexatetablet2.5 mg/1oralPd Rx Pharmaceuticals, Inc.1990-11-012016-04-05Us
Methotrexateinjection25 mg/mLintra-arterial; intramuscular; intrathecal; intravenousPfizer Laboratories Div Pfizer Inc.2012-03-302016-04-23Us
Methotrexateinjection, solution25 mg/mLintra-arterial; intramuscular; intrathecal; intravenousTeva Parenteral Medicines, Inc.2012-08-012016-04-05Us
Methotrexateinjection, solution1 g/40mLintra-arterial; intramuscular; intrathecal; intravenousMylan Institutional LLC2012-06-272016-04-05Us
Methotrexateinjection, solution25 mg/mLintra-arterial; intramuscular; intrathecal; intravenousPhysicians Total Care, Inc.2003-03-262016-04-05Us
Methotrexatetablet2.5 mg/1oralAv Kare, Inc.2014-11-202016-04-05Us
Methotrexateinjection25 mg/mLintra-arterial; intramuscular; intrathecal; intravenousPfizer Laboratories Div Pfizer Inc.2012-03-302016-04-23Us
Methotrexateinjection, solution25 mg/mLintra-arterial; intramuscular; intrathecal; intravenousTeva Parenteral Medicines, Inc.2012-07-312016-04-05Us
Methotrexatetablet2.5 mg/1oralRebel Distributors Corp1990-10-152016-04-05Us
Methotrexateinjection25 mg/mLintra-arterial; intramuscular; intrathecal; intravenousPfizer Laboratories Div Pfizer Inc.2012-03-302016-04-23Us
Methotrexateinjection25 mg/mLintra-arterial; intramuscular; intrathecal; intravenousAccord Healthcare, Inc.2014-02-012016-04-05Us
Methotrexateinjection25 mg/mLintra-arterial; intramuscular; intrathecal; intravenousPfizer Laboratories Div Pfizer Inc.2012-03-302016-04-23Us
Methotrexateinjection, solution25 mg/mLintra-arterial; intramuscular; intrathecal; intravenousTeva Parenteral Medicines, Inc.2012-08-012016-01-22Us
Methotrexateinjection25 mg/mLintra-arterial; intramuscular; intrathecal; intravenousPfizer Laboratories Div Pfizer Inc.2012-03-302016-04-23Us
Methotrexateinjection25 mg/mLintra-arterial; intramuscular; intrathecal; intravenousMylan Institutional LLC2012-03-302016-04-05Us
Methotrexateinjection, solution25 mg/mLintra-arterial; intramuscular; intravenousFresenius Kabi USA, LLC2001-09-102016-04-05Us
Methotrexatetablet2.5 mg/1oralBarr Laboratories Inc.1990-11-012016-04-23Us
Methotrexateinjection25 mg/mLintra-arterial; intramuscular; intrathecal; intravenousMylan Institutional LLC2012-03-302016-04-05Us
Methotrexate Sodiumtablet2.5 mg/1oralREMEDYREPACK INC.2011-07-212016-04-05Us
Methotrexate Sodiumtablet2.5 mg/1oralRoxane Laboratories, Inc1994-08-012016-04-23Us
Methotrexate Sodiumtablet2.5 mg/1oralREMEDYREPACK INC.2011-06-202016-04-05Us
Methotrexate Sodiuminjection, solution25 mg/mLintra-arterial; intramuscular; intrathecal; intravenousPfizer Laboratories Div Pfizer Inc.2012-03-302016-04-23Us
Methotrexate Sodiuminjection, solution25 mg/mLintra-arterial; intramuscular; intrathecal; intravenousMylan Institutional LLC2012-03-302016-04-05Us
Methotrexate Sodiumtablet2.5 mg/1oralPhysicians Total Care, Inc.2007-12-052016-04-05Us
Methotrexate Sodiuminjection, solution25 mg/mLintra-arterial; intramuscular; intrathecal; intravenousSandoz Inc2009-06-012016-04-05Us
Methotrexate Sodiuminjection, solution25 mg/mLintra-arterial; intramuscular; intrathecal; intravenousSandoz Inc2009-06-012016-04-05Us
Methotrexate Sodiumtablet2.5 mg/1oralbryant ranch prepack1994-08-012016-04-05Us
Methotrexate Sodiumtablet2.5 mg/1oralRoxane Laboratories, Inc1994-08-012016-04-23Us
Trexalltablet, film coated15 mg/1oralTeva Women's Health, Inc.2001-05-032016-04-05Us
Trexalltablet, film coated10 mg/1oralTeva Women's Health, Inc.2001-05-032016-04-05Us
Trexalltablet, film coated7.5 mg/1oralTeva Women's Health, Inc.2001-05-032016-04-05Us
Trexalltablet, film coated5 mg/1oralTeva Women's Health, Inc.2001-05-032016-04-05Us
Over the Counter ProductsNot Available
International Brands
NameCompany
AbitrexateTeva
AlltrexNaprod
ArtraitTRB
AtrexelSchering-Plough
BendatrexatBendalis
CarditrexCadila
DermotrexEast West
EbetrexEbewe
EmtexateNot Available
LedertrexateBiodim
MaxtrexPfizer
MeisushengHospira
MexateCadila HC
RheumatrexWyeth KK
TrexanAtafarm
ZexateDabur Pharma
Brand mixturesNot Available
Salts
Name/CASStructureProperties
Methotrexate Sodium
Thumb
  • InChI Key: DASQOOZCTWOQPA-GXKRWWSZSA-L
  • Monoisotopic Mass: 498.13520514
  • Average Mass: 498.4029
DBSALT000115
Categories
UNIIYL5FZ2Y5U1
CAS number59-05-2
WeightAverage: 454.4393
Monoisotopic: 454.171315854
Chemical FormulaC20H22N8O5
InChI KeyInChIKey=FBOZXECLQNJBKD-ZDUSSCGKSA-N
InChI
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
IUPAC Name
(2S)-2-[(4-{[(2,4-diaminopteridin-6-yl)methyl](methyl)amino}phenyl)formamido]pentanedioic acid
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
Taxonomy
DescriptionThis compound belongs to the class of organic compounds known as folic acids. These are heterocyclic compounds based on the 4-[(pteridin-6-ylmethyl)amino]benzoic acid skeleton conjugated with one or more L-glutamate units.
KingdomOrganic compounds
Super ClassOrganoheterocyclic compounds
ClassPteridines and derivatives
Sub ClassPterins and derivatives
Direct ParentFolic acids
Alternative Parents
Substituents
  • Folic acid
  • N-acyl-alpha amino acid or derivatives
  • N-acyl-alpha-amino acid
  • Hippuric acid
  • Hippuric acid or derivatives
  • Aminobenzoic acid or derivatives
  • Alpha-amino acid or derivatives
  • N-substituted-alpha-amino acid
  • Benzoic acid or derivatives
  • Benzamide
  • Aminobenzamide
  • Substituted aniline
  • Dialkylarylamine
  • Benzoyl
  • Aralkylamine
  • Aniline
  • Aminopyrimidine
  • Amino fatty acid
  • Fatty acyl
  • Imidolactam
  • Benzenoid
  • Pyrimidine
  • Pyrazine
  • Primary aromatic amine
  • Dicarboxylic acid or derivatives
  • Monocyclic benzene moiety
  • Heteroaromatic compound
  • Tertiary amine
  • Secondary carboxylic acid amide
  • Carboxamide group
  • Azacycle
  • Carboxylic acid
  • Carboxylic acid derivative
  • Hydrocarbon derivative
  • Primary amine
  • Organooxygen compound
  • Organonitrogen compound
  • Carbonyl group
  • Amine
  • Aromatic heteropolycyclic compound
Molecular FrameworkAromatic heteropolycyclic compounds
External Descriptors
Pharmacology
IndicationMethotrexate 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.
PharmacodynamicsMethotrexate 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 also indicated in the management of severe, active, classical, or definite rheumatoid arthritis.
Mechanism of actionMethotrexate 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.
Related Articles
AbsorptionOral 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.
Volume of distribution
  • 0.18 L/kg [initial volume of distribution (Vd)]
  • 0.4 – 0.8 L/kg [steady state Vd]
    Methotrexate competes with reduced folates for active transport across cell membranes by means of a single carrier-mediated active transport process. At serum concentrations greater than 100 micromolar, passive diffusion becomes a major pathway by which effective intracellular concentrations can be achieved. Methotrexate does not cross the blood-brain-barrier.
Protein binding50% bound to protein, primarily to albumin
Metabolism

Methotrexate undergoes hepatic and intracellular metabolism to polyglutamated forms which can be converted back to methotrexate by hydroxylase enzymes. These polyglutamates act as inhibitors of dihydrofolate reductase and thymidylate synthetase. A small amount of metabolism to 7-hydroxymethotrexate may occur at doses commonly prescribed. Furthermore, intestinal flora partially metabolizes methotrexate after oral administration.

SubstrateEnzymesProduct
Methotrexate
7-hydroxymethotrexateDetails
Route of eliminationRenal 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 lifeLow doses (less than 30 mg/m^2): 3 to 10 hours; High doses: 8 to 15 hours.
Clearance

Methotrexate clearance rates vary widely and are generally decreased at higher doses. Delayed drug clearance has been identified as one of the major factors responsible for methotrexate toxicity.

ToxicitySymptoms of overdose include bone marrow suppression and gastrointestinal toxicity. LD50=43mg/kg(orally in rat).
Affected organisms
  • Humans and other mammals
Pathways
PathwayCategorySMPDB ID
Methotrexate Action PathwayDrug actionSMP00432
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug Reactions
Interacting Gene/EnzymeSNP RS IDAllele nameDefining changeAdverse ReactionReference(s)
Canalicular multispecific organic anion transporter 1
Gene symbol: ABCC2
UniProt: Q92887
Not AvailableABCC2 IVS 23+56T alleleGeneral toxicity (gastrointestinal and hepatotoxicity)18381794
Methylenetetrahydrofolate reductase
Gene symbol: MTHFR
UniProt: P42898
rs1801133 Not AvailableT alleleMucositis, hepatic toxicity, thrombocytopenia, alopecia17488658
ADMET
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.8261
Blood Brain Barrier-0.9467
Caco-2 permeable-0.7754
P-glycoprotein substrateSubstrate0.8172
P-glycoprotein inhibitor INon-inhibitor0.7752
P-glycoprotein inhibitor IINon-inhibitor0.9879
Renal organic cation transporterNon-inhibitor0.8886
CYP450 2C9 substrateNon-substrate0.85
CYP450 2D6 substrateNon-substrate0.7968
CYP450 3A4 substrateSubstrate0.5177
CYP450 1A2 substrateNon-inhibitor0.9045
CYP450 2C9 inhibitorNon-inhibitor0.907
CYP450 2D6 inhibitorNon-inhibitor0.9231
CYP450 2C19 inhibitorNon-inhibitor0.9025
CYP450 3A4 inhibitorNon-inhibitor0.8333
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.9739
Ames testNon AMES toxic0.9132
CarcinogenicityNon-carcinogens0.9517
BiodegradationNot ready biodegradable0.9741
Rat acute toxicity3.4955 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9564
hERG inhibition (predictor II)Non-inhibitor0.6958
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397 )
Pharmacoeconomics
Manufacturers
  • Abic ltd
  • Pharmacia and upjohn co
  • Hospira inc
  • App pharmaceuticals llc
  • Abraxis pharmaceutical products
  • Bedford laboratories div ben venue laboratories inc
  • Norbrook laboratories ltd
  • Pharmachemie usa inc
  • Bioniche pharma usa llc
  • Ebewe pharma ges mbh nfg kg
  • Pharmachemie bv
  • Bristol laboratories inc div bristol myers co
  • Bristol myers co
  • Bristol myers squibb
  • Barr laboratories inc
  • Dava pharmaceuticals inc
  • Duramed pharmaceuticals inc sub barr laboratories inc
  • Mylan pharmaceuticals inc
  • Roxane laboratories inc
Packagers
Dosage forms
FormRouteStrength
Injectionintra-arterial; intramuscular; intrathecal; intravenous25 mg/mL
Injection, powder, lyophilized, for solutionintra-arterial; intramuscular; intrathecal; intravenous1 g/1
Injection, solutionintra-arterial; intramuscular; intrathecal; intravenous1 g/40mL
Injection, solutionintra-arterial; intramuscular; intravenous25 mg/mL
Tabletoral2.5 mg
Liquidintravenous10 mg
Liquidintravenous2.5 mg
Liquidintravenous25 mg
Solutionintra-arterial; intramuscular; intrathecal; intravenous15 mg
Solutionintra-arterial; intramuscular; intrathecal; intravenous20 mg
Solutionintra-arterial; intramuscular; intrathecal; intravenous7.5 mg
Solutionintra-arterial; intramuscular; intrathecal; intravenous10 mg
Solutionintra-arterial; intramuscular; intravenous25 mg
Solutionintravenous25 mg
Injection, solutionintra-arterial; intramuscular; intrathecal; intravenous25 mg/mL
Tabletoral2.5 mg/1
Powder for solutionintramuscular; intrathecal; intravenous20 mg
Liquidintramuscular; intrathecal; intravenous25 mg
Liquidintramuscular; intrathecal; intravenous50 mg
Liquidintra-arterial; intramuscular; intrathecal; intravenous25 mg
Solutionintra-arterial; intramuscular; intrathecal; intravenous25 mg
Solutionintra-arterial; intramuscular; intrathecal; intravenous; intraventricular25 mg
Tabletoral10 mg
Powder for solutionintra-arterial; intramuscular; intrathecal; intravenous20 mg
Solutionintra-arterial; intramuscular; intravenous10 mg
Solutionintra-arterial; intramuscular; intravenous15 mg
Solutionintra-arterial; intramuscular; intravenous20 mg
Solutionintra-arterial; intramuscular; intravenous7.5 mg
Injection, solutionsubcutaneous10 mg/.4mL
Injection, solutionsubcutaneous15 mg/.4mL
Injection, solutionsubcutaneous20 mg/.4mL
Injection, solutionsubcutaneous25 mg/.4mL
Injection, solutionsubcutaneous7.5 mg/.4mL
Injection, solutionsubcutaneous10 mg/.2mL
Injection, solutionsubcutaneous12.5 mg/.25mL
Injection, solutionsubcutaneous15 mg/.3mL
Injection, solutionsubcutaneous17.5 mg/.35mL
Injection, solutionsubcutaneous22.5 mg/.45mL
Injection, solutionsubcutaneous25 mg/.5mL
Injection, solutionsubcutaneous27.5 mg/.55mL
Injection, solutionsubcutaneous30 mg/.6mL
Injection, solutionsubcutaneous7.5 mg/.15mL
Tablet, film coatedoral10 mg/1
Tablet, film coatedoral15 mg/1
Tablet, film coatedoral5 mg/1
Tablet, film coatedoral7.5 mg/1
Prices
Unit descriptionCostUnit
Methotrexate powder261.33USD g
Rheumatrex 8 2.5 mg tablet Disp Pack169.98USD disp
Rheumatrex 24 2.5 mg tablet Disp Pack129.06USD disp
Rheumatrex 20 2.5 mg tablet Disp Pack107.59USD disp
Rheumatrex 12 2.5 mg tablet Disp Pack63.65USD disp
Methotrexate Sodium 25 mg/ml (pf) Solution 40ml Vial58.99USD vial
Trexall 15 mg tablet25.98USD tablet
Methotrexate Sodium 25 mg/ml (pf) Solution 10ml Vial24.99USD vial
Trexall 10 mg tablet17.67USD tablet
Methotrexate Sodium 25 mg/ml Solution 1 Vial = 2ml15.11USD vial
Methotrexate Sodium 25 mg/ml (pf) Solution 2ml Vial14.99USD vial
Trexall 7.5 mg tablet12.99USD tablet
Rheumatrex 2.5 mg tablet11.23USD tablet
Trexall 5 mg tablet8.66USD tablet
Methotrexate Sod. (Preserved) 25 mg/ml8.38USD ml
Methotrexate Sod.(Unpreserved) 25 mg/ml4.56USD ml
Methotrexate 2.5 mg tablet2.71USD tablet
Methotrexate 10 mg Tablet2.58USD tablet
Ratio-Methotrexate Sodium 2.5 mg Tablet0.66USD tablet
Apo-Methotrexate 2.5 mg Tablet0.66USD tablet
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US6746429 No2000-04-122020-04-12Us
US7744582 No1999-08-102019-08-10Us
US7776015 No1999-08-102019-08-10Us
US8021335 No2006-10-042026-10-04Us
US8480631 No2010-03-192030-03-19Us
US8562564 No2006-01-242026-01-24Us
US8579865 No2010-03-192030-03-19Us
US8664231 No2009-06-012029-06-01Us
US8945063 No2010-03-192030-03-19Us
USRE44846 No1999-08-102019-08-10Us
USRE44847 No1999-08-102019-08-10Us
Properties
StateSolid
Experimental Properties
PropertyValueSource
melting point195 °CNot Available
water solubility2600 mg/LNot Available
logP-1.85HANSCH,C ET AL. (1995)
Caco2 permeability-5.92ADME Research, USCD
pKa4.7SANGSTER (1994)
Predicted Properties
PropertyValueSource
Water Solubility0.171 mg/mLALOGPS
logP-0.91ALOGPS
logP-0.5ChemAxon
logS-3.4ALOGPS
pKa (Strongest Acidic)3.41ChemAxon
pKa (Strongest Basic)2.81ChemAxon
Physiological Charge-2ChemAxon
Hydrogen Acceptor Count12ChemAxon
Hydrogen Donor Count5ChemAxon
Polar Surface Area210.54 Å2ChemAxon
Rotatable Bond Count9ChemAxon
Refractivity119.21 m3·mol-1ChemAxon
Polarizability44.54 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability0ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Mass Spec (NIST)Download (10.1 KB)
Spectra
Spectrum TypeDescriptionSplash Key
MSMass Spectrum (Electron Ionization)splash10-qz10000000-25b0e287457fb3845ef4View in MoNA
1D NMR1H NMR SpectrumNot Available
1D NMR13C NMR SpectrumNot Available
References
Synthesis Reference

DrugSyn.org

US2512572
General References
  1. Klareskog L, van der Heijde D, de Jager JP, Gough A, Kalden J, Malaise M, Martin Mola E, Pavelka K, Sany J, Settas L, Wajdula J, Pedersen R, Fatenejad S, Sanda M: Therapeutic effect of the combination of etanercept and methotrexate compared with each treatment alone in patients with rheumatoid arthritis: double-blind randomised controlled trial. Lancet. 2004 Feb 28;363(9410):675-81. [PubMed:15001324 ]
  2. Johnston A, Gudjonsson JE, Sigmundsdottir H, Ludviksson BR, Valdimarsson H: The anti-inflammatory action of methotrexate is not mediated by lymphocyte apoptosis, but by the suppression of activation and adhesion molecules. Clin Immunol. 2005 Feb;114(2):154-63. [PubMed:15639649 ]
External Links
ATC CodesL01BA01L04AX03
AHFS Codes
  • 10:00.00
PDB Entries
FDA labelDownload (518 KB)
MSDSDownload (77 KB)
Interactions
Drug Interactions
Drug
Acetylsalicylic acidThe serum concentration of Methotrexate can be increased when it is combined with Acetylsalicylic acid.
AcitretinAcitretin may increase the hepatotoxic activities of Methotrexate.
AlitretinoinAlitretinoin may increase the hepatotoxic activities of Methotrexate.
AmdinocillinThe serum concentration of Methotrexate can be increased when it is combined with Amdinocillin.
AminophyllineThe serum concentration of Aminophylline can be increased when it is combined with Methotrexate.
Aminosalicylic AcidThe serum concentration of Methotrexate can be increased when it is combined with Aminosalicylic Acid.
AmoxicillinThe serum concentration of Methotrexate can be increased when it is combined with Amoxicillin.
AmpicillinThe serum concentration of Methotrexate can be increased when it is combined with Ampicillin.
AzidocillinThe serum concentration of Methotrexate can be increased when it is combined with Azidocillin.
AzlocillinThe serum concentration of Methotrexate can be increased when it is combined with Azlocillin.
BacampicillinThe serum concentration of Methotrexate can be increased when it is combined with Bacampicillin.
Benzathine benzylpenicillinThe serum concentration of Methotrexate can be increased when it is combined with Benzathine benzylpenicillin.
BenzylpenicillinThe serum concentration of Methotrexate can be increased when it is combined with Benzylpenicillin.
Bismuth SubsalicylateThe serum concentration of Methotrexate can be increased when it is combined with Bismuth Subsalicylate.
BumetanideThe therapeutic efficacy of Bumetanide can be decreased when used in combination with Methotrexate.
CarbenicillinThe serum concentration of Methotrexate can be increased when it is combined with Carbenicillin.
CelecoxibThe serum concentration of Methotrexate can be increased when it is combined with Celecoxib.
CholestyramineCholestyramine can cause a decrease in the absorption of Methotrexate resulting in a reduced serum concentration and potentially a decrease in efficacy.
CiprofloxacinThe serum concentration of Methotrexate can be increased when it is combined with Ciprofloxacin.
CloxacillinThe serum concentration of Methotrexate can be increased when it is combined with Cloxacillin.
ClozapineThe risk or severity of adverse effects can be increased when Methotrexate is combined with Clozapine.
ColesevelamColesevelam can cause a decrease in the absorption of Methotrexate resulting in a reduced serum concentration and potentially a decrease in efficacy.
ColestipolColestipol can cause a decrease in the absorption of Methotrexate resulting in a reduced serum concentration and potentially a decrease in efficacy.
CyclacillinThe serum concentration of Methotrexate can be increased when it is combined with Cyclacillin.
CyclosporineThe serum concentration of Methotrexate can be increased when it is combined with Cyclosporine.
DenosumabThe risk or severity of adverse effects can be increased when Denosumab is combined with Methotrexate.
DexketoprofenThe serum concentration of Methotrexate can be increased when it is combined with Dexketoprofen.
DiclofenacThe serum concentration of Methotrexate can be increased when it is combined with Diclofenac.
DicloxacillinThe serum concentration of Methotrexate can be increased when it is combined with Dicloxacillin.
DiflunisalThe serum concentration of Methotrexate can be increased when it is combined with Diflunisal.
DyphyllineThe serum concentration of Dyphylline can be increased when it is combined with Methotrexate.
EltrombopagThe serum concentration of Methotrexate can be increased when it is combined with Eltrombopag.
EsomeprazoleThe serum concentration of Methotrexate can be increased when it is combined with Esomeprazole.
Etacrynic acidThe therapeutic efficacy of Ethacrynic acid can be decreased when used in combination with Methotrexate.
EtodolacThe serum concentration of Methotrexate can be increased when it is combined with Etodolac.
FenoprofenThe serum concentration of Methotrexate can be increased when it is combined with Fenoprofen.
FloctafenineThe serum concentration of Methotrexate can be increased when it is combined with Floctafenine.
FlucloxacillinThe serum concentration of Methotrexate can be increased when it is combined with Flucloxacillin.
FlurbiprofenThe serum concentration of Methotrexate can be increased when it is combined with Flurbiprofen.
FoscarnetFoscarnet may increase the nephrotoxic activities of Methotrexate.
FosphenytoinThe serum concentration of Fosphenytoin can be decreased when it is combined with Methotrexate.
FurosemideThe therapeutic efficacy of Furosemide can be decreased when used in combination with Methotrexate.
HetacillinThe serum concentration of Methotrexate can be increased when it is combined with Hetacillin.
IbuprofenThe serum concentration of Methotrexate can be increased when it is combined with Ibuprofen.
IndomethacinThe serum concentration of Methotrexate can be increased when it is combined with Indomethacin.
InfliximabThe serum concentration of Methotrexate can be increased when it is combined with Infliximab.
KetoprofenThe serum concentration of Methotrexate can be increased when it is combined with Ketoprofen.
KetorolacThe serum concentration of Methotrexate can be increased when it is combined with Ketorolac.
LansoprazoleThe serum concentration of Methotrexate can be increased when it is combined with Lansoprazole.
LeflunomideThe risk or severity of adverse effects can be increased when Methotrexate is combined with Leflunomide.
LumacaftorThe serum concentration of Methotrexate can be decreased when it is combined with Lumacaftor.
Magnesium salicylateThe serum concentration of Methotrexate can be increased when it is combined with Magnesium salicylate.
Mefenamic acidThe serum concentration of Methotrexate can be increased when it is combined with Mefenamic acid.
MeloxicamThe serum concentration of Methotrexate can be increased when it is combined with Meloxicam.
MetamizoleThe risk or severity of adverse effects can be increased when Methotrexate is combined with Metamizole.
MeticillinThe serum concentration of Methotrexate can be increased when it is combined with Meticillin.
MezlocillinThe serum concentration of Methotrexate can be increased when it is combined with Mezlocillin.
MipomersenMipomersen may increase the hepatotoxic activities of Methotrexate.
NabumetoneThe serum concentration of Methotrexate can be increased when it is combined with Nabumetone.
NafcillinThe serum concentration of Methotrexate can be increased when it is combined with Nafcillin.
NaproxenThe serum concentration of Methotrexate can be increased when it is combined with Naproxen.
NatalizumabThe risk or severity of adverse effects can be increased when Methotrexate is combined with Natalizumab.
OmeprazoleThe serum concentration of Methotrexate can be increased when it is combined with Omeprazole.
OxacillinThe serum concentration of Methotrexate can be increased when it is combined with Oxacillin.
OxaprozinThe serum concentration of Methotrexate can be increased when it is combined with Oxaprozin.
PantoprazoleThe serum concentration of Methotrexate can be increased when it is combined with Pantoprazole.
PhenoxymethylpenicillinThe serum concentration of Methotrexate can be increased when it is combined with Phenoxymethylpenicillin.
PhenytoinThe serum concentration of Phenytoin can be decreased when it is combined with Methotrexate.
PimecrolimusThe risk or severity of adverse effects can be increased when Pimecrolimus is combined with Methotrexate.
PiperacillinThe serum concentration of Methotrexate can be increased when it is combined with Piperacillin.
PiroxicamThe serum concentration of Methotrexate can be increased when it is combined with Piroxicam.
PivampicillinThe serum concentration of Methotrexate can be increased when it is combined with Pivampicillin.
PivmecillinamThe serum concentration of Methotrexate can be increased when it is combined with Pivmecillinam.
ProbenecidThe serum concentration of Methotrexate can be increased when it is combined with Probenecid.
Procaine benzylpenicillinThe serum concentration of Methotrexate can be increased when it is combined with Procaine benzylpenicillin.
RabeprazoleThe serum concentration of Methotrexate can be increased when it is combined with Rabeprazole.
RanolazineThe serum concentration of Methotrexate can be increased when it is combined with Ranolazine.
RoflumilastRoflumilast may increase the immunosuppressive activities of Methotrexate.
RolapitantThe serum concentration of Methotrexate can be increased when it is combined with Rolapitant.
SalsalateThe serum concentration of Methotrexate can be increased when it is combined with Salsalate.
SaquinavirThe serum concentration of Methotrexate can be increased when it is combined with Saquinavir.
Sipuleucel-TThe therapeutic efficacy of Sipuleucel-T can be decreased when used in combination with Methotrexate.
SulfadiazineThe risk or severity of adverse effects can be increased when Sulfadiazine is combined with Methotrexate.
SulfasalazineSulfasalazine may increase the hepatotoxic activities of Methotrexate.
SulfisoxazoleThe risk or severity of adverse effects can be increased when Sulfisoxazole is combined with Methotrexate.
SulindacThe serum concentration of Methotrexate can be increased when it is combined with Sulindac.
TacrolimusThe risk or severity of adverse effects can be increased when Tacrolimus is combined with Methotrexate.
TegafurThe risk or severity of adverse effects can be increased when Methotrexate is combined with Tegafur.
TeriflunomideThe serum concentration of Methotrexate can be increased when it is combined with Teriflunomide.
TesmilifeneThe serum concentration of Methotrexate can be decreased when it is combined with Tesmilifene.
TetrahydrobiopterinThe serum concentration of Tetrahydrobiopterin can be decreased when it is combined with Methotrexate.
TheophyllineThe serum concentration of Theophylline can be increased when it is combined with Methotrexate.
Tiaprofenic acidThe serum concentration of Methotrexate can be increased when it is combined with Tiaprofenic acid.
TicarcillinThe serum concentration of Methotrexate can be increased when it is combined with Ticarcillin.
TofacitinibMethotrexate may increase the immunosuppressive activities of Tofacitinib.
TolmetinThe serum concentration of Methotrexate can be increased when it is combined with Tolmetin.
TorasemideThe therapeutic efficacy of Torasemide can be decreased when used in combination with Methotrexate.
TrastuzumabTrastuzumab may increase the neutropenic activities of Methotrexate.
TrimethoprimThe risk or severity of adverse effects can be increased when Trimethoprim is combined with Methotrexate.
VerapamilThe serum concentration of Methotrexate can be increased when it is combined with Verapamil.
Food Interactions
  • Milk appears to reduce its absorption.
  • Take without regard to meals. Limit caffeine intake.

Targets

Kind
Protein
Organism
Human
Pharmacological action
yes
Actions
inhibitor
General Function:
Nadph binding
Specific Function:
Key enzyme in folate metabolism. Contributes to the de novo mitochondrial thymidylate biosynthesis pathway. Catalyzes an essential reaction for de novo glycine and purine synthesis, and for DNA precursor synthesis. Binds its own mRNA and that of DHFRL1.
Gene Name:
DHFR
Uniprot ID:
P00374
Molecular Weight:
21452.61 Da
References
  1. Al-Rashood ST, Aboldahab IA, Nagi MN, Abouzeid LA, Abdel-Aziz AA, Abdel-Hamide SG, Youssef KM, Al-Obaid AM, El-Subbagh HI: Synthesis, dihydrofolate reductase inhibition, antitumor testing, and molecular modeling study of some new 4(3H)-quinazolinone analogs. Bioorg Med Chem. 2006 Dec 15;14(24):8608-21. Epub 2006 Sep 12. [PubMed:16971132 ]
  2. Assaraf YG: Molecular basis of antifolate resistance. Cancer Metastasis Rev. 2007 Mar;26(1):153-81. [PubMed:17333344 ]
  3. Bennett B, Langan P, Coates L, Mustyakimov M, Schoenborn B, Howell EE, Dealwis C: Neutron diffraction studies of Escherichia coli dihydrofolate reductase complexed with methotrexate. Proc Natl Acad Sci U S A. 2006 Dec 5;103(49):18493-8. Epub 2006 Nov 27. [PubMed:17130456 ]
  4. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352 ]
  5. Totani K, Matsuo I, Ihara Y, Ito Y: High-mannose-type glycan modifications of dihydrofolate reductase using glycan-methotrexate conjugates. Bioorg Med Chem. 2006 Aug 1;14(15):5220-9. Epub 2006 May 2. [PubMed:16647263 ]
  6. Uga H, Kuramori C, Ohta A, Tsuboi Y, Tanaka H, Hatakeyama M, Yamaguchi Y, Takahashi T, Kizaki M, Handa H: A new mechanism of methotrexate action revealed by target screening with affinity beads. Mol Pharmacol. 2006 Nov;70(5):1832-9. Epub 2006 Aug 25. [PubMed:16936229 ]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrate
General Function:
Xanthine dehydrogenase activity
Specific Function:
Oxidase with broad substrate specificity, oxidizing aromatic azaheterocycles, such as N1-methylnicotinamide and N-methylphthalazinium, as well as aldehydes, such as benzaldehyde, retinal, pyridoxal, and vanillin. Plays a key role in the metabolism of xenobiotics and drugs containing aromatic azaheterocyclic substituents. Participates in the bioactivation of prodrugs such as famciclovir, catalyz...
Gene Name:
AOX1
Uniprot ID:
Q06278
Molecular Weight:
147916.735 Da
References
  1. Zientek M, Jiang Y, Youdim K, Obach RS: In vitro-in vivo correlation for intrinsic clearance for drugs metabolized by human aldehyde oxidase. Drug Metab Dispos. 2010 Aug;38(8):1322-7. doi: 10.1124/dmd.110.033555. Epub 2010 May 5. [PubMed:20444863 ]
  2. Baggott JE, Morgan SL: Methotrexate catabolism to 7-hydroxymethotrexate in rheumatoid arthritis alters drug efficacy and retention and is reduced by folic acid supplementation. Arthritis Rheum. 2009 Aug;60(8):2257-61. doi: 10.1002/art.24685. [PubMed:19644884 ]
  3. Jordan CG, Rashidi MR, Laljee H, Clarke SE, Brown JE, Beedham C: Aldehyde oxidase-catalysed oxidation of methotrexate in the liver of guinea-pig, rabbit and man. J Pharm Pharmacol. 1999 Apr;51(4):411-8. [PubMed:10385213 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrate
General Function:
Protein complex binding
Specific Function:
Catalyzes the conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, a co-substrate for homocysteine remethylation to methionine.
Gene Name:
MTHFR
Uniprot ID:
P42898
Molecular Weight:
74595.895 Da
References
  1. Hider SL, Bruce IN, Thomson W: The pharmacogenetics of methotrexate. Rheumatology (Oxford). 2007 Oct;46(10):1520-4. Epub 2007 Jun 24. [PubMed:17586865 ]
  2. Kremer JM: Methotrexate pharmacogenomics. Ann Rheum Dis. 2006 Sep;65(9):1121-3. [PubMed:16905578 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
inhibitor
General Function:
Phosphogluconate dehydrogenase (decarboxylating) activity
Specific Function:
Catalyzes the oxidative decarboxylation of 6-phosphogluconate to ribulose 5-phosphate and CO(2), with concomitant reduction of NADP to NADPH.
Gene Name:
PGD
Uniprot ID:
P52209
Molecular Weight:
53139.56 Da
References
  1. Akkemik E, Budak H, Ciftci M: Effects of some drugs on human erythrocyte 6-phosphogluconate dehydrogenase: an in vitro study. J Enzyme Inhib Med Chem. 2010 Aug;25(4):476-9. doi: 10.3109/14756360903257900. [PubMed:20235752 ]
  2. Berman HM, Westbrook J, Feng Z, Gilliland G, Bhat TN, Weissig H, Shindyalov IN, Bourne PE: The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42. [PubMed:10592235 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrate
General Function:
Tetrahydrofolylpolyglutamate synthase activity
Specific Function:
Catalyzes conversion of folates to polyglutamate derivatives allowing concentration of folate compounds in the cell and the intracellular retention of these cofactors, which are important substrates for most of the folate-dependent enzymes that are involved in one-carbon transfer reactions involved in purine, pyrimidine and amino acid synthesis. Unsubstituted reduced folates are the preferred s...
Gene Name:
FPGS
Uniprot ID:
Q05932
Molecular Weight:
64608.53 Da
References
  1. Hider SL, Bruce IN, Thomson W: The pharmacogenetics of methotrexate. Rheumatology (Oxford). 2007 Oct;46(10):1520-4. Epub 2007 Jun 24. [PubMed:17586865 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrate
General Function:
Omega peptidase activity
Specific Function:
Hydrolyzes the polyglutamate sidechains of pteroylpolyglutamates. Progressively removes gamma-glutamyl residues from pteroylpoly-gamma-glutamate to yield pteroyl-alpha-glutamate (folic acid) and free glutamate. May play an important role in the bioavailability of dietary pteroylpolyglutamates and in the metabolism of pteroylpolyglutamates and antifolates.
Gene Name:
GGH
Uniprot ID:
Q92820
Molecular Weight:
35964.045 Da
References
  1. Hider SL, Bruce IN, Thomson W: The pharmacogenetics of methotrexate. Rheumatology (Oxford). 2007 Oct;46(10):1520-4. Epub 2007 Jun 24. [PubMed:17586865 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrate
General Function:
Nadph binding
Specific Function:
Key enzyme in folate metabolism. Contributes to the de novo mitochondrial thymidylate biosynthesis pathway. Catalyzes an essential reaction for de novo glycine and purine synthesis, and for DNA precursor synthesis. Binds its own mRNA and that of DHFRL1.
Gene Name:
DHFR
Uniprot ID:
P00374
Molecular Weight:
21452.61 Da
References
  1. Hider SL, Bruce IN, Thomson W: The pharmacogenetics of methotrexate. Rheumatology (Oxford). 2007 Oct;46(10):1520-4. Epub 2007 Jun 24. [PubMed:17586865 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrate
General Function:
Thymidylate synthase activity
Specific Function:
Contributes to the de novo mitochondrial thymidylate biosynthesis pathway.
Gene Name:
TYMS
Uniprot ID:
P04818
Molecular Weight:
35715.65 Da
References
  1. Hider SL, Bruce IN, Thomson W: The pharmacogenetics of methotrexate. Rheumatology (Oxford). 2007 Oct;46(10):1520-4. Epub 2007 Jun 24. [PubMed:17586865 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
inhibitor
General Function:
Protein homodimerization activity
Specific Function:
Bifunctional enzyme that catalyzes 2 steps in purine biosynthesis.Promotes insulin receptor/INSR autophosphorylation and is involved in INSR internalization (PubMed:25687571).
Gene Name:
ATIC
Uniprot ID:
P31939
Molecular Weight:
64615.255 Da
References
  1. Hider SL, Bruce IN, Thomson W: The pharmacogenetics of methotrexate. Rheumatology (Oxford). 2007 Oct;46(10):1520-4. Epub 2007 Jun 24. [PubMed:17586865 ]

Carriers

Kind
Protein
Organism
Human
Pharmacological action
no
General Function:
Toxic substance binding
Specific Function:
Serum albumin, the main protein of plasma, has a good binding capacity for water, Ca(2+), Na(+), K(+), fatty acids, hormones, bilirubin and drugs. Its main function is the regulation of the colloidal osmotic pressure of blood. Major zinc transporter in plasma, typically binds about 80% of all plasma zinc.
Gene Name:
ALB
Uniprot ID:
P02768
Molecular Weight:
69365.94 Da
References
  1. Warnecke A, Fichtner I, Sass G, Kratz F: Synthesis, cleavage profile, and antitumor efficacy of an albumin-binding prodrug of methotrexate that is cleaved by plasmin and cathepsin B. Arch Pharm (Weinheim). 2007 Aug;340(8):389-95. [PubMed:17628030 ]
  2. Xie WJ, Feng YP, Cao SL, Zhao YF: [Study of the interaction between methotrexate and bovine serum albumin by spectrometry]. Guang Pu Xue Yu Guang Pu Fen Xi. 2006 Oct;26(10):1876-9. [PubMed:17205742 ]

Transporters

Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrateinhibitor
General Function:
Organic anion transmembrane transporter activity
Specific Function:
May act as an inducible transporter in the biliary and intestinal excretion of organic anions. Acts as an alternative route for the export of bile acids and glucuronides from cholestatic hepatocytes (By similarity).
Gene Name:
ABCC3
Uniprot ID:
O15438
Molecular Weight:
169341.14 Da
References
  1. Akita H, Suzuki H, Hirohashi T, Takikawa H, Sugiyama Y: Transport activity of human MRP3 expressed in Sf9 cells: comparative studies with rat MRP3. Pharm Res. 2002 Jan;19(1):34-41. [PubMed:11837698 ]
  2. Oleschuk CJ, Deeley RG, Cole SP: Substitution of Trp1242 of TM17 alters substrate specificity of human multidrug resistance protein 3. Am J Physiol Gastrointest Liver Physiol. 2003 Feb;284(2):G280-9. Epub 2002 Oct 9. [PubMed:12388190 ]
  3. Hirohashi T, Suzuki H, Sugiyama Y: Characterization of the transport properties of cloned rat multidrug resistance-associated protein 3 (MRP3). J Biol Chem. 1999 May 21;274(21):15181-5. [PubMed:10329726 ]
  4. Zeng H, Liu G, Rea PA, Kruh GD: Transport of amphipathic anions by human multidrug resistance protein 3. Cancer Res. 2000 Sep 1;60(17):4779-84. [PubMed:10987286 ]
  5. Zeng H, Chen ZS, Belinsky MG, Rea PA, Kruh GD: Transport of methotrexate (MTX) and folates by multidrug resistance protein (MRP) 3 and MRP1: effect of polyglutamylation on MTX transport. Cancer Res. 2001 Oct 1;61(19):7225-32. [PubMed:11585759 ]
  6. Paumi CM, Wright M, Townsend AJ, Morrow CS: Multidrug resistance protein (MRP) 1 and MRP3 attenuate cytotoxic and transactivating effects of the cyclopentenone prostaglandin, 15-deoxy-Delta(12,14)prostaglandin J2 in MCF7 breast cancer cells. Biochemistry. 2003 May 13;42(18):5429-37. [PubMed:12731885 ]
  7. Li T, Ito K, Horie T: Transport of fluorescein methotrexate by multidrug resistance-associated protein 3 in IEC-6 cells. Am J Physiol Gastrointest Liver Physiol. 2003 Sep;285(3):G602-10. [PubMed:12909565 ]
  8. Zehnpfennig B, Urbatsch IL, Galla HJ: Functional reconstitution of human ABCC3 into proteoliposomes reveals a transport mechanism with positive cooperativity. Biochemistry. 2009 May 26;48(20):4423-30. doi: 10.1021/bi9001908. [PubMed:19334674 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrateinhibitor
General Function:
Atpase activity, coupled to transmembrane movement of substances
Specific Function:
May be an organic anion pump relevant to cellular detoxification.
Gene Name:
ABCC4
Uniprot ID:
O15439
Molecular Weight:
149525.33 Da
References
  1. Chen ZS, Lee K, Kruh GD: Transport of cyclic nucleotides and estradiol 17-beta-D-glucuronide by multidrug resistance protein 4. Resistance to 6-mercaptopurine and 6-thioguanine. J Biol Chem. 2001 Sep 7;276(36):33747-54. Epub 2001 Jul 10. [PubMed:11447229 ]
  2. Rius M, Nies AT, Hummel-Eisenbeiss J, Jedlitschky G, Keppler D: Cotransport of reduced glutathione with bile salts by MRP4 (ABCC4) localized to the basolateral hepatocyte membrane. Hepatology. 2003 Aug;38(2):374-84. [PubMed:12883481 ]
  3. Bai J, Lai L, Yeo HC, Goh BC, Tan TM: Multidrug resistance protein 4 (MRP4/ABCC4) mediates efflux of bimane-glutathione. Int J Biochem Cell Biol. 2004 Feb;36(2):247-57. [PubMed:14643890 ]
  4. van Aubel RA, Smeets PH, Peters JG, Bindels RJ, Russel FG: The MRP4/ABCC4 gene encodes a novel apical organic anion transporter in human kidney proximal tubules: putative efflux pump for urinary cAMP and cGMP. J Am Soc Nephrol. 2002 Mar;13(3):595-603. [PubMed:11856762 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrateinhibitor
General Function:
Transporter activity
Specific Function:
Mediates export of organic anions and drugs from the cytoplasm. Mediates ATP-dependent transport of glutathione and glutathione conjugates, leukotriene C4, estradiol-17-beta-o-glucuronide, methotrexate, antiviral drugs and other xenobiotics. Confers resistance to anticancer drugs. Hydrolyzes ATP with low efficiency.
Gene Name:
ABCC1
Uniprot ID:
P33527
Molecular Weight:
171589.5 Da
References
  1. Heijn M, Hooijberg JH, Scheffer GL, Szabo G, Westerhoff HV, Lankelma J: Anthracyclines modulate multidrug resistance protein (MRP) mediated organic anion transport. Biochim Biophys Acta. 1997 May 22;1326(1):12-22. [PubMed:9188796 ]
  2. Zeng H, Chen ZS, Belinsky MG, Rea PA, Kruh GD: Transport of methotrexate (MTX) and folates by multidrug resistance protein (MRP) 3 and MRP1: effect of polyglutamylation on MTX transport. Cancer Res. 2001 Oct 1;61(19):7225-32. [PubMed:11585759 ]
  3. Paumi CM, Wright M, Townsend AJ, Morrow CS: Multidrug resistance protein (MRP) 1 and MRP3 attenuate cytotoxic and transactivating effects of the cyclopentenone prostaglandin, 15-deoxy-Delta(12,14)prostaglandin J2 in MCF7 breast cancer cells. Biochemistry. 2003 May 13;42(18):5429-37. [PubMed:12731885 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrateinhibitor
General Function:
Sodium-independent organic anion transmembrane transporter activity
Specific Function:
Involved in the renal elimination of endogenous and exogenous organic anions. Functions as organic anion exchanger when the uptake of one molecule of organic anion is coupled with an efflux of one molecule of endogenous dicarboxylic acid (glutarate, ketoglutarate, etc). Mediates the sodium-independent uptake of 2,3-dimercapto-1-propanesulfonic acid (DMPS) (By similarity). Mediates the sodium-in...
Gene Name:
SLC22A6
Uniprot ID:
Q4U2R8
Molecular Weight:
61815.78 Da
References
  1. Lu R, Chan BS, Schuster VL: Cloning of the human kidney PAH transporter: narrow substrate specificity and regulation by protein kinase C. Am J Physiol. 1999 Feb;276(2 Pt 2):F295-303. [PubMed:9950961 ]
  2. Kuze K, Graves P, Leahy A, Wilson P, Stuhlmann H, You G: Heterologous expression and functional characterization of a mouse renal organic anion transporter in mammalian cells. J Biol Chem. 1999 Jan 15;274(3):1519-24. [PubMed:9880528 ]
  3. Uwai Y, Okuda M, Takami K, Hashimoto Y, Inui K: Functional characterization of the rat multispecific organic anion transporter OAT1 mediating basolateral uptake of anionic drugs in the kidney. FEBS Lett. 1998 Nov 6;438(3):321-4. [PubMed:9827570 ]
  4. Takeda M, Khamdang S, Narikawa S, Kimura H, Hosoyamada M, Cha SH, Sekine T, Endou H: Characterization of methotrexate transport and its drug interactions with human organic anion transporters. J Pharmacol Exp Ther. 2002 Aug;302(2):666-71. [PubMed:12130730 ]
  5. Sekine T, Watanabe N, Hosoyamada M, Kanai Y, Endou H: Expression cloning and characterization of a novel multispecific organic anion transporter. J Biol Chem. 1997 Jul 25;272(30):18526-9. [PubMed:9228014 ]
  6. Uwai Y, Iwamoto K: Transport of aminopterin by human organic anion transporters hOAT1 and hOAT3: Comparison with methotrexate. Drug Metab Pharmacokinet. 2010;25(2):163-9. [PubMed:20460822 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
inhibitor
General Function:
Atpase activity, coupled to transmembrane movement of substances
Specific Function:
ATP-dependent transporter probably involved in cellular detoxification through lipophilic anion extrusion.
Gene Name:
ABCC10
Uniprot ID:
Q5T3U5
Molecular Weight:
161627.375 Da
References
  1. Chen ZS, Hopper-Borge E, Belinsky MG, Shchaveleva I, Kotova E, Kruh GD: Characterization of the transport properties of human multidrug resistance protein 7 (MRP7, ABCC10). Mol Pharmacol. 2003 Feb;63(2):351-8. [PubMed:12527806 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrateinhibitor
General Function:
Sodium-independent organic anion transmembrane transporter activity
Specific Function:
Plays an important role in the excretion/detoxification of endogenous and exogenous organic anions, especially from the brain and kidney. Involved in the transport basolateral of steviol, fexofenadine. Transports benzylpenicillin (PCG), estrone-3-sulfate (E1S), cimetidine (CMD), 2,4-dichloro-phenoxyacetate (2,4-D), p-amino-hippurate (PAH), acyclovir (ACV) and ochratoxin (OTA).
Gene Name:
SLC22A8
Uniprot ID:
Q8TCC7
Molecular Weight:
59855.585 Da
References
  1. Ohtsuki S, Kikkawa T, Mori S, Hori S, Takanaga H, Otagiri M, Terasaki T: Mouse reduced in osteosclerosis transporter functions as an organic anion transporter 3 and is localized at abluminal membrane of blood-brain barrier. J Pharmacol Exp Ther. 2004 Jun;309(3):1273-81. Epub 2004 Feb 4. [PubMed:14762099 ]
  2. Kusuhara H, Sekine T, Utsunomiya-Tate N, Tsuda M, Kojima R, Cha SH, Sugiyama Y, Kanai Y, Endou H: Molecular cloning and characterization of a new multispecific organic anion transporter from rat brain. J Biol Chem. 1999 May 7;274(19):13675-80. [PubMed:10224140 ]
  3. Cha SH, Sekine T, Fukushima JI, Kanai Y, Kobayashi Y, Goya T, Endou H: Identification and characterization of human organic anion transporter 3 expressing predominantly in the kidney. Mol Pharmacol. 2001 May;59(5):1277-86. [PubMed:11306713 ]
  4. Takeda M, Khamdang S, Narikawa S, Kimura H, Hosoyamada M, Cha SH, Sekine T, Endou H: Characterization of methotrexate transport and its drug interactions with human organic anion transporters. J Pharmacol Exp Ther. 2002 Aug;302(2):666-71. [PubMed:12130730 ]
  5. Uwai Y, Iwamoto K: Transport of aminopterin by human organic anion transporters hOAT1 and hOAT3: Comparison with methotrexate. Drug Metab Pharmacokinet. 2010;25(2):163-9. [PubMed:20460822 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrateinhibitor
General Function:
Organic anion transmembrane transporter activity
Specific Function:
Mediates hepatobiliary excretion of numerous organic anions. May function as a cellular cisplatin transporter.
Gene Name:
ABCC2
Uniprot ID:
Q92887
Molecular Weight:
174205.64 Da
References
  1. Han YH, Kato Y, Haramura M, Ohta M, Matsuoka H, Sugiyama Y: Physicochemical parameters responsible for the affinity of methotrexate analogs for rat canalicular multispecific organic anion transporter (cMOAT/MRP2). Pharm Res. 2001 May;18(5):579-86. [PubMed:11465411 ]
  2. Masuda M, I'izuka Y, Yamazaki M, Nishigaki R, Kato Y, Ni'inuma K, Suzuki H, Sugiyama Y: Methotrexate is excreted into the bile by canalicular multispecific organic anion transporter in rats. Cancer Res. 1997 Aug 15;57(16):3506-10. [PubMed:9270020 ]
  3. Hooijberg JH, Broxterman HJ, Kool M, Assaraf YG, Peters GJ, Noordhuis P, Scheper RJ, Borst P, Pinedo HM, Jansen G: Antifolate resistance mediated by the multidrug resistance proteins MRP1 and MRP2. Cancer Res. 1999 Jun 1;59(11):2532-5. [PubMed:10363967 ]
  4. Bakos E, Evers R, Sinko E, Varadi A, Borst P, Sarkadi B: Interactions of the human multidrug resistance proteins MRP1 and MRP2 with organic anions. Mol Pharmacol. 2000 Apr;57(4):760-8. [PubMed:10727523 ]
  5. Chen C, Scott D, Hanson E, Franco J, Berryman E, Volberg M, Liu X: Impact of Mrp2 on the biliary excretion and intestinal absorption of furosemide, probenecid, and methotrexate using Eisai hyperbilirubinemic rats. Pharm Res. 2003 Jan;20(1):31-7. [PubMed:12608533 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrate
General Function:
Xenobiotic-transporting atpase activity
Specific Function:
Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells.
Gene Name:
ABCB1
Uniprot ID:
P08183
Molecular Weight:
141477.255 Da
References
  1. Norris MD, De Graaf D, Haber M, Kavallaris M, Madafiglio J, Gilbert J, Kwan E, Stewart BW, Mechetner EB, Gudkov AV, Roninson IB: Involvement of MDR1 P-glycoprotein in multifactorial resistance to methotrexate. Int J Cancer. 1996 Mar 1;65(5):613-9. [PubMed:8598312 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrate
General Function:
Sodium-independent organic anion transmembrane transporter activity
Specific Function:
Mediates the Na(+)-independent transport of organic anions such as sulfobromophthalein (BSP) and conjugated (taurocholate) and unconjugated (cholate) bile acids (By similarity). Selectively inhibited by the grapefruit juice component naringin.
Gene Name:
SLCO1A2
Uniprot ID:
P46721
Molecular Weight:
74144.105 Da
References
  1. Cattori V, van Montfoort JE, Stieger B, Landmann L, Meijer DK, Winterhalter KH, Meier PJ, Hagenbuch B: Localization of organic anion transporting polypeptide 4 (Oatp4) in rat liver and comparison of its substrate specificity with Oatp1, Oatp2 and Oatp3. Pflugers Arch. 2001 Nov;443(2):188-95. [PubMed:11713643 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrate
General Function:
Symporter activity
Specific Function:
Proton-coupled monocarboxylate transporter. Catalyzes the rapid transport across the plasma membrane of many monocarboxylates such as lactate, pyruvate, branched-chain oxo acids derived from leucine, valine and isoleucine, and the ketone bodies acetoacetate, beta-hydroxybutyrate and acetate. Depending on the tissue and on cicumstances, mediates the import or export of lactic acid and ketone bod...
Gene Name:
SLC16A1
Uniprot ID:
P53985
Molecular Weight:
53943.685 Da
References
  1. Tamai I, Sai Y, Ono A, Kido Y, Yabuuchi H, Takanaga H, Satoh E, Ogihara T, Amano O, Izeki S, Tsuji A: Immunohistochemical and functional characterization of pH-dependent intestinal absorption of weak organic acids by the monocarboxylic acid transporter MCT1. J Pharm Pharmacol. 1999 Oct;51(10):1113-21. [PubMed:10579682 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrate
General Function:
Purine nucleotide transmembrane transporter activity
Specific Function:
Participates in physiological processes involving bile acids, conjugated steroids and cyclic nucleotides. Enhances the cellular extrusion of cAMP and cGMP. Stimulates the ATP-dependent uptake of a range of physiological and synthetic lipophilic anions, including the glutathione S-conjugates leukotriene C4 and dinitrophenyl S-glutathione, steroid sulfates such as dehydroepiandrosterone 3-sulfate...
Gene Name:
ABCC11
Uniprot ID:
Q96J66
Molecular Weight:
154299.625 Da
References
  1. Chen ZS, Guo Y, Belinsky MG, Kotova E, Kruh GD: Transport of bile acids, sulfated steroids, estradiol 17-beta-D-glucuronide, and leukotriene C4 by human multidrug resistance protein 8 (ABCC11). Mol Pharmacol. 2005 Feb;67(2):545-57. Epub 2004 Nov 10. [PubMed:15537867 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrate
General Function:
Sodium-independent organic anion transmembrane transporter activity
Specific Function:
Mediates the Na(+)-independent uptake of organic anions such as 17-beta-glucuronosyl estradiol, taurocholate, triiodothyronine (T3), leukotriene C4, dehydroepiandrosterone sulfate (DHEAS), methotrexate and sulfobromophthalein (BSP). Involved in the clearance of bile acids and organic anions from the liver.
Gene Name:
SLCO1B3
Uniprot ID:
Q9NPD5
Molecular Weight:
77402.175 Da
References
  1. Abe T, Unno M, Onogawa T, Tokui T, Kondo TN, Nakagomi R, Adachi H, Fujiwara K, Okabe M, Suzuki T, Nunoki K, Sato E, Kakyo M, Nishio T, Sugita J, Asano N, Tanemoto M, Seki M, Date F, Ono K, Kondo Y, Shiiba K, Suzuki M, Ohtani H, Shimosegawa T, Iinuma K, Nagura H, Ito S, Matsuno S: LST-2, a human liver-specific organic anion transporter, determines methotrexate sensitivity in gastrointestinal cancers. Gastroenterology. 2001 Jun;120(7):1689-99. [PubMed:11375950 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrate
General Function:
Sodium-independent organic anion transmembrane transporter activity
Specific Function:
Mediates saturable uptake of estrone sulfate, dehydroepiandrosterone sulfate and related compounds.
Gene Name:
SLC22A11
Uniprot ID:
Q9NSA0
Molecular Weight:
59970.945 Da
References
  1. Takeda M, Khamdang S, Narikawa S, Kimura H, Hosoyamada M, Cha SH, Sekine T, Endou H: Characterization of methotrexate transport and its drug interactions with human organic anion transporters. J Pharmacol Exp Ther. 2002 Aug;302(2):666-71. [PubMed:12130730 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrate
General Function:
Thyroid hormone transmembrane transporter activity
Specific Function:
Mediates the Na(+)-independent high affinity transport of organic anions such as the thyroid hormones thyroxine (T4) and rT3. Other potential substrates, such as triiodothyronine (T3), 17-beta-glucuronosyl estradiol, estrone-3-sulfate and sulfobromophthalein (BSP) are transported with much lower efficiency. May play a signifiant role in regulating T4 flux into and out of the brain (By similarity).
Gene Name:
SLCO1C1
Uniprot ID:
Q9NYB5
Molecular Weight:
78695.625 Da
References
  1. Pizzagalli F, Hagenbuch B, Stieger B, Klenk U, Folkers G, Meier PJ: Identification of a novel human organic anion transporting polypeptide as a high affinity thyroxine transporter. Mol Endocrinol. 2002 Oct;16(10):2283-96. [PubMed:12351693 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrate
General Function:
Sodium-independent organic anion transmembrane transporter activity
Specific Function:
Mediates the Na(+)-independent transport of organic anions such as estrone-3-sulfate (PubMed:10873595). Mediates transport of prostaglandins (PG) E1 and E2, thyroxine (T4), deltorphin II, BQ-123 and vasopressin, but not DPDPE (a derivative of enkephalin lacking an N-terminal tyrosine residue), estrone-3-sulfate, taurocholate, digoxin nor DHEAS (PubMed:16971491).
Gene Name:
SLCO3A1
Uniprot ID:
Q9UIG8
Molecular Weight:
76552.135 Da
References
  1. Adachi H, Suzuki T, Abe M, Asano N, Mizutamari H, Tanemoto M, Nishio T, Onogawa T, Toyohara T, Kasai S, Satoh F, Suzuki M, Tokui T, Unno M, Shimosegawa T, Matsuno S, Ito S, Abe T: Molecular characterization of human and rat organic anion transporter OATP-D. Am J Physiol Renal Physiol. 2003 Dec;285(6):F1188-97. [PubMed:14631946 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrate
General Function:
Xenobiotic-transporting atpase activity
Specific Function:
High-capacity urate exporter functioning in both renal and extrarenal urate excretion. Plays a role in porphyrin homeostasis as it is able to mediates the export of protoporhyrin IX (PPIX) both from mitochondria to cytosol and from cytosol to extracellular space, and cellular export of hemin, and heme. Xenobiotic transporter that may play an important role in the exclusion of xenobiotics from t...
Gene Name:
ABCG2
Uniprot ID:
Q9UNQ0
Molecular Weight:
72313.47 Da
References
  1. Suzuki M, Suzuki H, Sugimoto Y, Sugiyama Y: ABCG2 transports sulfated conjugates of steroids and xenobiotics. J Biol Chem. 2003 Jun 20;278(25):22644-9. Epub 2003 Apr 7. [PubMed:12682043 ]
  2. Breedveld P, Zelcer N, Pluim D, Sonmezer O, Tibben MM, Beijnen JH, Schinkel AH, van Tellingen O, Borst P, Schellens JH: Mechanism of the pharmacokinetic interaction between methotrexate and benzimidazoles: potential role for breast cancer resistance protein in clinical drug-drug interactions. Cancer Res. 2004 Aug 15;64(16):5804-11. [PubMed:15313923 ]
  3. Mitomo H, Kato R, Ito A, Kasamatsu S, Ikegami Y, Kii I, Kudo A, Kobatake E, Sumino Y, Ishikawa T: A functional study on polymorphism of the ATP-binding cassette transporter ABCG2: critical role of arginine-482 in methotrexate transport. Biochem J. 2003 Aug 1;373(Pt 3):767-74. [PubMed:12741957 ]
  4. Chen ZS, Robey RW, Belinsky MG, Shchaveleva I, Ren XQ, Sugimoto Y, Ross DD, Bates SE, Kruh GD: Transport of methotrexate, methotrexate polyglutamates, and 17beta-estradiol 17-(beta-D-glucuronide) by ABCG2: effects of acquired mutations at R482 on methotrexate transport. Cancer Res. 2003 Jul 15;63(14):4048-54. [PubMed:12874005 ]
  5. Volk EL, Schneider E: Wild-type breast cancer resistance protein (BCRP/ABCG2) is a methotrexate polyglutamate transporter. Cancer Res. 2003 Sep 1;63(17):5538-43. [PubMed:14500392 ]
  6. Suzuki K, Doki K, Homma M, Tamaki H, Hori S, Ohtani H, Sawada Y, Kohda Y: Co-administration of proton pump inhibitors delays elimination of plasma methotrexate in high-dose methotrexate therapy. Br J Clin Pharmacol. 2009 Jan;67(1):44-9. doi: 10.1111/j.1365-2125.2008.03303.x. Epub 2008 Nov 17. [PubMed:19076159 ]
  7. Hou YX, Li CZ, Palaniyandi K, Magtibay PM, Homolya L, Sarkadi B, Chang XB: Effects of putative catalytic base mutation E211Q on ABCG2-mediated methotrexate transport. Biochemistry. 2009 Sep 29;48(38):9122-31. doi: 10.1021/bi900675v. [PubMed:19691360 ]
  8. Tiwari AK, Sodani K, Wang SR, Kuang YH, Ashby CR Jr, Chen X, Chen ZS: Nilotinib (AMN107, Tasigna) reverses multidrug resistance by inhibiting the activity of the ABCB1/Pgp and ABCG2/BCRP/MXR transporters. Biochem Pharmacol. 2009 Jul 15;78(2):153-61. doi: 10.1016/j.bcp.2009.04.002. Epub 2009 Apr 11. [PubMed:19427995 ]
  9. Dai CL, Liang YJ, Wang YS, Tiwari AK, Yan YY, Wang F, Chen ZS, Tong XZ, Fu LW: Sensitization of ABCG2-overexpressing cells to conventional chemotherapeutic agent by sunitinib was associated with inhibiting the function of ABCG2. Cancer Lett. 2009 Jun 28;279(1):74-83. doi: 10.1016/j.canlet.2009.01.027. Epub 2009 Feb 18. [PubMed:19232821 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrate
General Function:
Sodium-independent organic anion transmembrane transporter activity
Specific Function:
Mediates sodium-independent multispecific organic anion transport. Transport of prostaglandin E2, prostaglandin F2, tetracycline, bumetanide, estrone sulfate, glutarate, dehydroepiandrosterone sulfate, allopurinol, 5-fluorouracil, paclitaxel, L-ascorbic acid, salicylate, ethotrexate, and alpha-ketoglutarate.
Gene Name:
SLC22A7
Uniprot ID:
Q9Y694
Molecular Weight:
60025.025 Da
References
  1. Sun W, Wu RR, van Poelje PD, Erion MD: Isolation of a family of organic anion transporters from human liver and kidney. Biochem Biophys Res Commun. 2001 May 4;283(2):417-22. [PubMed:11327718 ]
  2. Sekine T, Cha SH, Tsuda M, Apiwattanakul N, Nakajima N, Kanai Y, Endou H: Identification of multispecific organic anion transporter 2 expressed predominantly in the liver. FEBS Lett. 1998 Jun 12;429(2):179-82. [PubMed:9650585 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrate
General Function:
Sodium-independent organic anion transmembrane transporter activity
Specific Function:
Mediates the Na(+)-independent uptake of organic anions such as pravastatin, taurocholate, methotrexate, dehydroepiandrosterone sulfate, 17-beta-glucuronosyl estradiol, estrone sulfate, prostaglandin E2, thromboxane B2, leukotriene C3, leukotriene E4, thyroxine and triiodothyronine. Involved in the clearance of bile acids and organic anions from the liver.
Gene Name:
SLCO1B1
Uniprot ID:
Q9Y6L6
Molecular Weight:
76447.99 Da
References
  1. Abe T, Unno M, Onogawa T, Tokui T, Kondo TN, Nakagomi R, Adachi H, Fujiwara K, Okabe M, Suzuki T, Nunoki K, Sato E, Kakyo M, Nishio T, Sugita J, Asano N, Tanemoto M, Seki M, Date F, Ono K, Kondo Y, Shiiba K, Suzuki M, Ohtani H, Shimosegawa T, Iinuma K, Nagura H, Ito S, Matsuno S: LST-2, a human liver-specific organic anion transporter, determines methotrexate sensitivity in gastrointestinal cancers. Gastroenterology. 2001 Jun;120(7):1689-99. [PubMed:11375950 ]
  2. van de Steeg E, van der Kruijssen CM, Wagenaar E, Burggraaff JE, Mesman E, Kenworthy KE, Schinkel AH: Methotrexate pharmacokinetics in transgenic mice with liver-specific expression of human organic anion-transporting polypeptide 1B1 (SLCO1B1). Drug Metab Dispos. 2009 Feb;37(2):277-81. doi: 10.1124/dmd.108.024315. Epub 2008 Nov 20. [PubMed:19022939 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrateinhibitor
General Function:
Methotrexate transporter activity
Specific Function:
Has been shown to act both as an intestinal proton-coupled high-affinity folate transporter and as an intestinal heme transporter which mediates heme uptake from the gut lumen into duodenal epithelial cells. The iron is then released from heme and may be transported into the bloodstream. Dietary heme iron is an important nutritional source of iron. Shows a higher affinity for folate than heme.
Gene Name:
SLC46A1
Uniprot ID:
Q96NT5
Molecular Weight:
49770.04 Da
References
  1. Nakai Y, Inoue K, Abe N, Hatakeyama M, Ohta KY, Otagiri M, Hayashi Y, Yuasa H: Functional characterization of human proton-coupled folate transporter/heme carrier protein 1 heterologously expressed in mammalian cells as a folate transporter. J Pharmacol Exp Ther. 2007 Aug;322(2):469-76. Epub 2007 May 2. [PubMed:17475902 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
General Function:
Sodium-independent organic anion transmembrane transporter activity
Specific Function:
Organic anion transporter, capable of transporting pharmacological substances such as digoxin, ouabain, thyroxine, methotrexate and cAMP. May participate in the regulation of membrane transport of ouabain. Involved in the uptake of the dipeptidyl peptidase-4 inhibitor sitagliptin and hence may play a role in its transport into and out of renal proximal tubule cells. May be involved in the first...
Gene Name:
SLCO4C1
Uniprot ID:
Q6ZQN7
Molecular Weight:
78947.525 Da
References
  1. Mikkaichi T, Suzuki T, Onogawa T, Tanemoto M, Mizutamari H, Okada M, Chaki T, Masuda S, Tokui T, Eto N, Abe M, Satoh F, Unno M, Hishinuma T, Inui K, Ito S, Goto J, Abe T: Isolation and characterization of a digoxin transporter and its rat homologue expressed in the kidney. Proc Natl Acad Sci U S A. 2004 Mar 9;101(10):3569-74. Epub 2004 Mar 1. [PubMed:14993604 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrate
General Function:
Reduced folate carrier activity
Specific Function:
Transporter for the intake of folate. Uptake of folate in human placental choriocarcinoma cells occurs by a novel mechanism called potocytosis which functionally couples three components, namely the folate receptor, the folate transporter, and a V-type H(+)-pump.
Gene Name:
SLC19A1
Uniprot ID:
P41440
Molecular Weight:
64867.62 Da
References
  1. Qiu A, Jansen M, Sakaris A, Min SH, Chattopadhyay S, Tsai E, Sandoval C, Zhao R, Akabas MH, Goldman ID: Identification of an intestinal folate transporter and the molecular basis for hereditary folate malabsorption. Cell. 2006 Dec 1;127(5):917-28. [PubMed:17129779 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrate
General Function:
Receptor activity
Specific Function:
Binds to folate and reduced folic acid derivatives and mediates delivery of 5-methyltetrahydrofolate and folate analogs into the interior of cells. Has high affinity for folate and folic acid analogs at neutral pH. Exposure to slightly acidic pH after receptor endocytosis triggers a conformation change that strongly reduces its affinity for folates and mediates their release. Required for norma...
Gene Name:
FOLR1
Uniprot ID:
P15328
Molecular Weight:
29818.94 Da
References
  1. Sharma S, Das M, Kumar A, Marwaha V, Shankar S, Aneja R, Grover R, Arya V, Dhir V, Gupta R, Kumar U, Juyal RC, B K T: Interaction of genes from influx-metabolism-efflux pathway and their influence on methotrexate efficacy in rheumatoid arthritis patients among Indians. Pharmacogenet Genomics. 2008 Dec;18(12):1041-9. [PubMed:19093297 ]
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Drug created on June 13, 2005 07:24 / Updated on April 28, 2016 02:30