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Identification
Name Methotrexate
Accession Number DB00563 (APRD00353)
Type small molecule
Groups approved
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
Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure
Synonyms
Amethopterin
Amethopterine
HDMTX
L-Amethopterin
Methopterin
Methotextrate
Methotrexat
Methotrexate Sodium
Methylaminopterin
Methylaminopterinum
MTX
N-Bismethylpteroylglutamic Acid
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Salts Not Available
Brand names
Name Company
Abitrexate
Antifolan
Arbitrexate
Emtexate
Folex
Ledertrexate
Metatrexan
Methotrate
Mexate
Rheumatrex
Trexall
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Brand mixtures Not Available
Categories
  • Antineoplastic Agents
  • Antirheumatic Agents
  • Antimetabolites
  • Enzyme Inhibitors
  • Folic Acid Antagonists
  • Dermatologic Agents
  • Immunosuppressive Agents
  • Nucleic Acid Synthesis Inhibitors
  • Abortifacient Agents, Nonsteroidal
  • Abortifacient Agents
  • Antimetabolites, Antineoplastic
CAS number 59-05-2
Weight Average: 454.4393
Monoisotopic: 454.171315854
Chemical Formula C20H22N8O5
InChI Key InChIKey=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
Plain Text
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
Plain Text
Mass Spec show (10.1 KB)
Taxonomy
Kingdom Organic
Classes
  • Pterins
  • Keto-Acids
Substructures
  • Pterins
  • Hydroxy Compounds
  • Acetates
  • Amino Ketones
  • Aliphatic and Aryl Amines
  • Benzene and Derivatives
  • Carboxylic Acids and Derivatives
  • Pyrimidines and Derivatives
  • Pyrazines
  • Heterocyclic compounds
  • Aromatic compounds
  • Keto-Acids
  • Carboxamides and Derivatives
  • Pteridines
  • Imines
  • Benzoyl Derivatives
  • Cyanamides
  • Benzamides
  • Anilines
Pharmacology
Indication For the treatment of gestational choriocarcinoma, chorioadenoma destruens and hydatidiform mole. Also for the treatment of severe psoriasis and severe, active, classical or definite rheumatoid arthritis.
Pharmacodynamics 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 also indicated in the management of severe, active, classical, or definite rheumatoid arthritis.
Mechanism of action Methotrexate 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.
Absorption Generally well absorbed with a mean bioavailability of about 60%.
Volume of distribution
  • 0.4 to 0.8 L/kg
Protein binding 50%, primarily to albumin
Metabolism Hepatic.
Route of elimination With 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 life Low doses: 3 to 10 hours; High doses: 8 to 15 hours.
Clearance Not Available
Toxicity Symptoms of overdose include bone marrow suppression and gastrointestinal toxicity. LD50=43mg/kg(orally in rat).
Affected organisms
  • Humans and other mammals
Pathways
Pathway Name SMPDB ID
Smp00432 Methotrexate Pathway SMP00432
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
Form Route Strength
Solution Intramuscular
Solution Intrathecal
Solution Intravenous
Tablet Oral
Prices
Unit description Cost Unit
Methotrexate powder 261.33 USD g
Rheumatrex 8 2.5 mg tablet Disp Pack 169.98 USD disp
Rheumatrex 24 2.5 mg tablet Disp Pack 129.06 USD disp
Rheumatrex 20 2.5 mg tablet Disp Pack 107.59 USD disp
Rheumatrex 12 2.5 mg tablet Disp Pack 63.65 USD disp
Methotrexate Sodium 25 mg/ml (pf) Solution 40ml Vial 58.99 USD vial
Trexall 15 mg tablet 25.98 USD tablet
Methotrexate Sodium 25 mg/ml (pf) Solution 10ml Vial 24.99 USD vial
Trexall 10 mg tablet 17.67 USD tablet
Methotrexate Sodium 25 mg/ml Solution 1 Vial = 2ml 15.11 USD vial
Methotrexate Sodium 25 mg/ml (pf) Solution 2ml Vial 14.99 USD vial
Trexall 7.5 mg tablet 12.99 USD tablet
Rheumatrex 2.5 mg tablet 11.23 USD tablet
Trexall 5 mg tablet 8.66 USD tablet
Methotrexate Sod. (Preserved) 25 mg/ml 8.38 USD ml
Methotrexate Sod.(Unpreserved) 25 mg/ml 4.56 USD ml
Methotrexate 2.5 mg tablet 2.71 USD tablet
Methotrexate 10 mg Tablet 2.58 USD tablet
Ratio-Methotrexate Sodium 2.5 mg Tablet 0.66 USD tablet
Apo-Methotrexate 2.5 mg Tablet 0.66 USD tablet
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DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents Not Available
Properties
State solid
Experimental Properties
Property Value Source
melting point 195 °C Not Available
water solubility 2600 mg/L Not Available
logP -1.85 HANSCH,C ET AL. (1995)
Caco2 permeability -5.92 ADME Research, USCD
pKa 4.7 SANGSTER (1994)
Predicted Properties
Property Value Source
water solubility 1.71e-01 g/l ALOGPS
logP -0.91 ALOGPS
logP -0.5 ChemAxon
logS -3.4 ALOGPS
pKa (strongest acidic) 3.41 ChemAxon
pKa (strongest basic) 2.81 ChemAxon
physiological charge -2 ChemAxon
hydrogen acceptor count 12 ChemAxon
hydrogen donor count 5 ChemAxon
polar surface area 210.54 ChemAxon
rotatable bond count 9 ChemAxon
refractivity 119.21 ChemAxon
polarizability 44.54 ChemAxon
References
Synthesis Reference Not Available
General Reference
  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
  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
External Links
Resource Link
KEGG Drug D00142 Link_out
KEGG Compound C01937 Link_out
PubChem Compound 126941 Link_out
PubChem Substance 46507678 Link_out
ChemSpider 112728 Link_out
BindingDB 18050 Link_out
ChEBI 6837 Link_out
ChEMBL 6837 Link_out
Therapeutic Targets Database DNC000933 Link_out
PharmGKB PA450428 Link_out
HET MTX Link_out
Drug Product Database 2244798 Link_out
RxList http://www.rxlist.com/cgi/generic/mtx.htm Link_out
Drugs.com http://www.drugs.com/methotrexate.html Link_out
PDRhealth http://www.pdrhealth.com/drug_info/rxdrugprofiles/drugs/met1257.shtml Link_out
Wikipedia http://en.wikipedia.org/wiki/Methotrexate Link_out
ATC Codes
  • L01BA01
  • L04AX03
AHFS Codes
  • 10:00.00
PDB Entries
FDA label show (518 KB)
MSDS show (77 KB)
Interactions
Drug Interactions
Drug Interaction
Acetylsalicylic acid Acetylsalicylic acid increases the effect and toxicity of methotrexate.
Acitretin Acitretin/etretinate increases the effect and toxicity of methotrexate
Amoxicillin The penicillin increases the effect and toxicity of methotrexate
Ampicillin The penicillin increases the effect and toxicity of methotrexate
Bacampicillin The penicillin increases the effect and toxicity of methotrexate
Bismuth Subsalicylate The salicylate, bismuth subsalicylate, increases the effect and toxicity of methotrexate.
Carbenicillin The penicillin increases the effect and toxicity of methotrexate
Cholestyramine Decreased levels of methotrexate
Ciprofloxacin Ciprofloxacine may decrease the metabolism of methotrexate. Monitor for changes adverse effects of methotrexate if ciprofloxacin is initiated.
Cisplatin Cisplatin increases methotrexate toxicity
Clavulanate The penicillin increases the effect and toxicity of methotrexate
Cloxacillin The penicillin increases the effect and toxicity of methotrexate
Cyclosporine Cyclosporine may increase the effect and toxicity of methotrexate.
Diclofenac The NSAID, diclofenac, may decrease the renal excretion of methotrexate. Increased risk of methotrexate toxicity.
Dicloxacillin The penicillin increases the effect and toxicity of methotrexate
Diflunisal The NSAID, diflunisal, may decrease the renal excretion of methotrexate. Increased risk of methotrexate toxicity.
Digoxin The antineoplasic agent decreases the effect of digoxin
Doxycycline The tetracycline, doxycycline, may increase methotrexate toxicity.
Eltrombopag Increases levels of Methotrexate via metabolism decrease. OATP transporter protein inhibition.
Ethotoin The antineoplasic agent decreases the effect of hydantoin
Etodolac The NSAID, etodolac, may decrease the renal excretion of methotrexate. Increased risk of methotrexate toxicity.
Etretinate Acitretin/etretinate increases the effect and toxicity of methotrexate
Fenoprofen The NSAID, fenoprofen, may decrease the renal excretion of methotrexate. Increased risk of methotrexate toxicity.
Flucloxacillin The penicillin increases the effect and toxicity of methotrexate
Flurbiprofen The NSAID, flurbiprofen, may decrease the renal excretion of methotrexate. Increased risk of methotrexate toxicity.
Fosphenytoin The antineoplasic agent decreases the effect of hydantoin
Hydroxychloroquine Hydroxychloroquine increases the effect and toxicity of methotrexate
Ibuprofen The NSAID, ibuprofen, may decrease the renal excretion of methotrexate. Increased risk of methotrexate toxicity.
Indomethacin The NSAID, indomethacin, may decrease the renal excretion of methotrexate. Increased risk of methotrexate toxicity.
Ketoprofen The NSAID, ketoprofen, may decrease the renal excretion of methotrexate. Increased risk of methotrexate toxicity.
Ketorolac The NSAID, ketorolac, may decrease the renal excretion of methotrexate. Increased risk of methotrexate toxicity.
Magnesium salicylate The salicylate, magnesium salicylate, increases the effect and toxicity of methotrexate.
Meclofenamic acid The NSAID, meclofenamic acid, may decrease the renal excretion of methotrexate. Increased risk of methotrexate toxicity.
Mefenamic acid The NSAID, mefenamic acid, may decrease the renal excretion of methotrexate. Increased risk of methotrexate toxicity.
Mephenytoin The antineoplasic agent decreases the effect of hydantoin
Methicillin Acyl-Serine The penicillin increases the effect and toxicity of methotrexate
Mezlocillin The penicillin increases the effect and toxicity of methotrexate
Nabumetone The NSAID, nabumetone, may decrease the renal excretion of methotrexate. Increased risk of methotrexate toxicity.
Nafcillin The penicillin increases the effect and toxicity of methotrexate
Naproxen The NSAID, naproxen, may decrease the renal excretion of methotrexate. Increased risk of methotrexate toxicity.
Omeprazole Omeprazole increases the levels of methotrexate
Oxaprozin The NSAID, oxaprozin, may decrease the renal excretion of methotrexate. Increased risk of methotrexate toxicity.
Penicillin G The penicillin increases the effect and toxicity of methotrexate
Penicillin V The penicillin increases the effect and toxicity of methotrexate
Phenylbutazone The NSAID, phenylbutazone, may decrease the renal excretion of methotrexate. Increased risk of methotrexate toxicity.
Phenytoin The antineoplasic agent decreases the effect of hydantoin
Piperacillin The penicillin increases the effect and toxicity of methotrexate
Piroxicam The NSAID, piroxicam, may decrease the renal excretion of methotrexate. Increased risk of methotrexate toxicity.
Pivampicillin The penicillin increases the effect and toxicity of methotrexate
Probenecid Probenecid increases the effect and toxicity of methotrexate
Procarbazine Increased nephrotoxicity with this combination
Rilonacept Rilonacept and methotrexate both increase immunosuppressive effects; combination may increase risk of myelosuppression.
Rofecoxib Rofecoxib increases the levels of methotrexate
Salicylate-sodium The salicylate, salicylate-sodium, increases the effect and toxicity of methotrexate.
Salsalate The salicylate, salsalate, increases the effect and toxicity of methotrexate.
Sulfacytine The sulfamide increases the toxicity of methotrexate
Sulfadiazine The sulfamide increases the toxicity of methotrexate
Sulfadimethoxine The sulfamide increases the toxicity of methotrexate
Sulfadoxine The sulfamide increases the toxicity of methotrexate
Sulfamerazine The sulfamide increases the toxicity of methotrexate
Sulfamethazine The sulfamide increases the toxicity of methotrexate
Sulfamethizole The sulfamide increases the toxicity of methotrexate
Sulfamethoxazole The sulfamide increases the toxicity of methotrexate
Sulfapyridine The sulfamide increases the toxicity of methotrexate
Sulfathiazole The sulfamide increases the toxicity of methotrexate
Sulfisoxazole The sulfamide increases the toxicity of methotrexate
Sulindac The NSAID, sulindac, may decrease the clearance methotrexate. Consider alternate therapy, especially in patients receiving high antineoplastic doses of methotrexate. Otherwise, monitor for hematologic and renal toxicities.
Tenoxicam Tenoxicam may increase the serum concentration of Methotrexate by reducing renal tubular secretion of Methotrexate. Monitor for changes in Methotrexate therapeutic and adverse effects if Tenoxicam is initiated, discontinued or dose changed.
Tetracycline Tetracycline may increase methotrexate toxicity.
Tiaprofenic acid Tiaprofenic acid may decrease renal excretion of methotrexate. Consider alternate therapy or monitor for methotrexate toxicity.
Ticarcillin The penicillin increases the effect and toxicity of methotrexate
Tolmetin Tolmetin may decrease the renal excretion of Methotrexate. Alternate therapy should be considered. Otherwise, monitor for hemotologic and renal toxicities.
Trastuzumab Trastuzumab may increase the risk of neutropenia and anemia. Monitor closely for signs and symptoms of adverse events.
Trimethoprim Trimethoprim may increase the adverse/toxic effects of Methotrexate (e.g. bone marrow suppression). Concomitant use should be avoided or closely monitored for Methotrexate toxicity.
Trisalicylate-choline The salicylate, trisalicylate-choline, increases the effect and toxicity of methotrexate.
Food Interactions
  • Milk appears to reduce its absorption.
  • Take without regard to meals. Limit caffeine intake.
Targets

1. Dihydrofolate reductase

Pharmacological action: yes
Actions: inhibitor
Organism class: human
UniProt ID: P00374 Link_out
Gene: DHFR Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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
  2. Assaraf YG: Molecular basis of antifolate resistance. Cancer Metastasis Rev. 2007 Mar;26(1):153-81. Pubmed
  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
  4. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed
  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
  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
Enzymes

1. Methylenetetrahydrofolate reductase

Actions: substrate

Catalyzes the conversion of 5,10- methylenetetrahydrofolate to 5-methyltetrahydrofolate, a co- substrate for homocysteine remethylation to methionine

UniProt ID: P42898 Link_out
Gene: MTHFR Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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
  2. Kremer JM: Methotrexate pharmacogenomics. Ann Rheum Dis. 2006 Sep;65(9):1121-3. Pubmed

2. Aldehyde oxidase

Actions: substrate

An aldehyde + H(2)O + O(2) = a carboxylic acid + H(2)O(2)

UniProt ID: Q06278 Link_out
Gene: AOX1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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. Epub 2010 May 5. Pubmed
  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. Pubmed
  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

3. 6-phosphogluconate dehydrogenase, decarboxylating

Actions: inhibitor

6-phospho-D-gluconate + NADP(+) = D-ribulose 5-phosphate + CO(2) + NADPH

UniProt ID: P52209 Link_out
Gene: PGD Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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 Mar 17. Pubmed
  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

4. Folylpolyglutamate synthase, mitochondrial

Actions: substrate

Conversion of folates to polyglutamate derivatives. This allows tissues to concentrate folate at higher levels than in plasma

UniProt ID: Q05932 Link_out
Gene: FPGS Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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

5. Gamma-glutamyl hydrolase

Actions: substrate

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

UniProt ID: Q92820 Link_out
Gene: GGH Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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

6. Dihydrofolate reductase

Actions: substrate
UniProt ID: P00374 Link_out
Gene: DHFR Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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

7. Thymidylate synthase

Actions: substrate
UniProt ID: P04818 Link_out
Gene: TYMS Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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

8. Bifunctional purine biosynthesis protein PURH [Includes: Phosphoribosylaminoimidazolecarboxamide formyltransferase

Actions: inhibitor

10-formyltetrahydrofolate + 5-amino-1-(5- phospho-D-ribosyl)imidazole-4-carboxamide = tetrahydrofolate + 5- formamido-1-(5-phospho-D-ribosyl)imidazole-4-carboxamide

UniProt ID: P31939 Link_out
Gene: ATIC Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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
Transporters

1. Canalicular multispecific organic anion transporter 2

Actions: substrate, inhibitor

May act as an inducible transporter in the biliary and intestinal excretion of organic anions

UniProt ID: O15438 Link_out
Gene: ABCC3 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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
  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
  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
  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
  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
  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
  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
  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. Pubmed

2. Multidrug resistance-associated protein 4

Actions: substrate, inhibitor

May be an organic anion pump relevant to cellular detoxification

UniProt ID: O15439 Link_out
Gene: ABCC4 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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
  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
  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
  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

3. Multidrug resistance-associated protein 1

Actions: substrate, inhibitor

May participate directly in the active transport of drugs into subcellular organelles or influence drug distribution indirectly. Confers resistance to anticancer drugs. Transports LTC4. May protect milk against xenobiotics

UniProt ID: P33527 Link_out
Gene: ABCC1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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
  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
  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

4. Solute carrier family 22 member 6

Actions: substrate, inhibitor
UniProt ID: Q4U2R8 Link_out
Gene: hROAT1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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
  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
  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
  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
  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
  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

5. Multidrug resistance-associated protein 7

Actions: inhibitor

ATP-dependent transporter probably involved in cellular detoxification through lipophilic anion extrusion

UniProt ID: Q5T3U5 Link_out
Gene: ABCC10 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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

6. Solute carrier family 22 member 8

Actions: substrate, inhibitor

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)

UniProt ID: Q8TCC7 Link_out
Gene: SLC22A8 Link_out
Protein Sequence: FASTA
SNPs: SNPJam Report Link_out

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
  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
  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
  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
  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

7. Canalicular multispecific organic anion transporter 1

Actions: substrate, inhibitor

Mediates hepatobiliary excretion of numerous organic anions. May function as a cellular cisplatin transporter

UniProt ID: Q92887 Link_out
Gene: ABCC2 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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
  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
  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
  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
  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

8. Multidrug resistance protein 1

Actions: substrate

Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells

UniProt ID: P08183 Link_out
Gene: ABCB1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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

9. Solute carrier organic anion transporter family member 1A2

Actions: substrate

Mediates the Na(+)-independent transport of organic anions such as sulfobromophthalein (BSP) and conjugated (taurocholate) and unconjugated (cholate) bile acids (By similarity)

UniProt ID: P46721 Link_out
Gene: SLCO1A2 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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

10. Monocarboxylate transporter 1

Actions: substrate

Proton-linked 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

UniProt ID: P53985 Link_out
Gene: SLC16A1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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

11. ATP-binding cassette transporter sub-family C member 11

Actions: substrate

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 (DHEAS) and estrone 3-sulfate, glucuronides such as estradiol 17-beta-D-glucuronide (E(2)17betaG), the monoanionic bile acids glycocholate and taurocholate, and methotrexate. Probably functions to secrete earwax

UniProt ID: Q96J66 Link_out
Gene: ABCC11 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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

12. Solute carrier organic anion transporter family member 1B3

Actions: substrate

Mediates the Na(+)-independent transport of organic anions such as 17-beta-glucuronosyl estradiol, taurocholate, triiodothyronine (T3), leukotriene C4, dehydroepiandrosterone sulfate (DHEAS), methotrexate and sulfobromophthalein (BSP)

UniProt ID: Q9NPD5 Link_out
Gene: SLCO1B3 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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

13. Solute carrier family 22 member 11

Actions: substrate

Mediates saturable uptake of estrone sulfate, dehydroepiandrosterone sulfate and related compounds

UniProt ID: Q9NSA0 Link_out
Gene: SLC22A11 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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

14. Solute carrier organic anion transporter family member 1C1

Actions: substrate

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

UniProt ID: Q9NYB5 Link_out
Gene: SLCO1C1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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

15. Solute carrier organic anion transporter family member 3A1

Actions: substrate

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)

UniProt ID: Q9UIG8 Link_out
Gene: SLCO3A1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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

16. ATP-binding cassette sub-family G member 2

Actions: substrate

Xenobiotic transporter that may play an important role in the exclusion of xenobiotics from the brain. May be involved in brain-to-blood efflux. Appears to play a major role in the multidrug resistance phenotype of several cancer cell lines. When overexpressed, the transfected cells become resistant to mitoxantrone, daunorubicin and doxorubicin, display diminished intracellular accumulation of daunorubicin, and manifest an ATP- dependent increase in the efflux of rhodamine 123

UniProt ID: Q9UNQ0 Link_out
Gene: ABCG2 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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
  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
  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
  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
  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
  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. Epub 2008 Nov 17. Pubmed
  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. Pubmed
  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. Epub 2009 Apr 11. Pubmed
  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. Epub 2009 Feb 18. Pubmed

17. Solute carrier family 22 member 7

Actions: substrate

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

UniProt ID: Q9Y694 Link_out
Gene: SLC22A7 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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
  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

18. Solute carrier organic anion transporter family member 1B1

Actions: substrate

Mediates the Na(+)-independent transport 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. May play an important role in the clearance of bile acids and organic anions from the liver

UniProt ID: Q9Y6L6 Link_out
Gene: SLCO1B1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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
  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. Epub 2008 Nov 20. Pubmed

19. Heme carrier protein 1

Actions: substrate, inhibitor

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

UniProt ID: Q96NT5 Link_out
Gene: SLC46A1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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

20. Solute carrier organic anion transporter family member 4C1

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 step of the transport pathway of digoxin and various compounds into the urine in the kidney. May be involved in sperm maturation by enabling directed movement of organic anions and compounds within or between cells. This ion- transporting process is important to maintain the strict epididymal homeostasis necessary for sperm maturation. May have a role in secretory functions since seminal vesicle epithelial cells are assumed to secrete proteins involved in decapacitation by modifying surface proteins to facilitate the acquisition of the ability to fertilize the egg

UniProt ID: Q6ZQN7 Link_out
Gene: SLCO4C1 Link_out
Protein Sequence: FASTA
SNPs: SNPJam Report Link_out

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
Carriers

1. Serum albumin

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

UniProt ID: P02768 Link_out
Gene: ALB Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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
  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
Comments
Drug created on June 13, 2005 07:24 / Updated on February 08, 2013 16:19