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Identification
Name Trimethoprim
Accession Number DB00440 (APRD00103)
Type small molecule
Groups approved
Description

A pyrimidine inhibitor of dihydrofolate reductase, it is an antibacterial related to pyrimethamine. The interference with folic acid metabolism may cause a depression of hematopoiesis. It is potentiated by sulfonamides and the trimethoprim-sulfamethoxazole combination is the form most often used. It is sometimes used alone as an antimalarial. Trimethoprim resistance has been reported. [PubChem]
Structure Thumb
Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure
Synonyms Not Available
Brand names
  • Abacin
  • Abaprim
  • Alprim
  • Apo-Sulfatrim
  • Bactin
  • Bactramin
  • Bactrim
  • Bactrim DS
  • Bactrim Pediatric
  • Baktar
  • Chemotrim
  • Co-Trimoxazole
  • Comox
  • Cotrim
  • Cotrim D.S.
  • Drylin
  • Eusaprim
  • Fectrim
  • Gantaprim
  • Gantrim
  • Idotrim
  • Imexim
  • Instalac
  • Ipral
  • Kepinol
  • Laratrim
  • Lidaprim
  • Methoprim
  • Microtrim
  • Monoprim
  • Monotrim
  • Monotrimin
  • Nopil
  • Oraprim
  • Priloprim
  • Primosept
  • Primsol
  • Proloprim
  • Septra
  • Septra DS
  • Septra Grape
  • Septrin
  • Sigaprim
  • Sulfamethoprim
  • Sulfamethoprim-DS
  • Sulfamethoxazole & Trimethoprim
  • Sulfatrim
  • Sulfatrim Pediatric
  • Sulfatrim-DS
  • Sulfatrim-SS
  • Sulfotrim
  • Sulmeprim
  • Sulmeprim Pediatric
  • Sulprim
  • Sumetrolim
  • Supracombin
  • Suprim
  • Syraprim
  • Teleprim
  • Thiocuran
  • Tiempe
  • Tmp-Ratiopharm
  • Trigonyl
  • Trimanyl
  • Trimesulf
  • Trimeth/Sulfa
  • Trimethioprim
  • Trimethopriom
  • Trimetoprim
  • Trimexazole
  • Trimogal
  • Trimopan
  • Trimpex
  • Trimpex 200
  • Triprim
  • Unitrim
  • Uretrim
  • Uro-Septra
  • Uroplus
  • Uroplus DS
  • Uroplus SS
  • Wellcoprim
Brand name mixtures Not Available
Categories
  • Anti-Infectives
  • Antimalarials
  • Folic Acid Antagonists
  • Anti-Infective Agents, Urinary
CAS number 738-70-5
Weight Average: 290.3177
Monoisotopic: 290.137890462
Chemical Formula C14H18N4O3
InChI Key InChIKey=IEDVJHCEMCRBQM-UHFFFAOYSA-N
InChI
InChI=1S/C14H18N4O3/c1-19-10-5-8(6-11(20-2)12(10)21-3)4-9-7-17-14(16)18-13(9)15/h5-7H,4H2,1-3H3,(H4,15,16,17,18)
Plain Text
IUPAC Name
5-[(3,4,5-trimethoxyphenyl)methyl]pyrimidine-2,4-diamine
SMILES
COC1=CC(CC2=CN=C(N)N=C2N)=CC(OC)=C1OC
Plain Text
Mass Spec Not Available
Taxonomy
Kingdom Organic
Classes
  • Phenols and Derivatives
  • Ethers
  • Catechols
  • Anisoles
  • Phenyl Esters
Substructures
  • Phenols and Derivatives
  • Aliphatic and Aryl Amines
  • Ethers
  • Benzene and Derivatives
  • Pyrimidines and Derivatives
  • Catechols
  • Heterocyclic compounds
  • Aromatic compounds
  • Anisoles
  • Cyanamides
  • Phenyl Esters
Pharmacology
Indication For the treatment of urinary tract infections, uncomplicated pyelonephritis (with sulfamethoxazole) and mild acute prostatitis. May be used as pericoital (with sulfamethoxazole) or continuous prophylaxis in females with recurrent cystitis. May be used as an alternative to treat asymptomatic bacteriuria during pregnancy (only before the last 6 weeks of pregnancy). Other uses include: alternative agent in respiratory tract infections (otitis, sinusitus, bronchitis and pneumonia), treatment of Pneumocystis jirovecii pneumonia (acute or prophylaxis), Nocardia infections, and traveller's diarrhea.
Pharmacodynamics Trimethoprim is a pyrimidine analogue that disrupts folate synthesis, an essential part of the thymidine synthesis pathway. Inhibition of the enzyme starves the bacteria of nucleotides necessary for DNA replication.The drug, therefore, exhibits bactericidal activity.
Mechanism of action Trimethoprim binds to dihydrofolate reductase and inhibits the reduction of dihydrofolic acid (DHF) to tetrahydrofolic acid (THF). THF is an essential precursor in the thymidine synthesis pathway and interference with this pathway inhibits bacterial DNA synthesis. Trimethoprim's affinity for bacterial dihydrofolate reductase is several thousand times greater than its affinity for human dihydrofolate reductase. Sulfamethoxazole inhibits dihydrofolate synthetase (aka dihydropteroate synthetase), an enzyme involved further upstream in the same pathway. Trimethoprim and sulfamethoxazole are commonly used in combination due to their synergistic effects. This drug combination also reduces the development of resistance that is seen when either drug is used alone.
Absorption Readily and almost completely absorbed in the GI tract with peak serum concentrations attained 1-4 hours after oral administration. Widely distributed to tissues and fluids including kidney, lung, seminal fluid, aqueous humour, middle ear fluid, sputum, vaginal secretions, bile, bone and CSF.
Volume of distribution Not Available
Protein binding 42-46% bound to plasma proteins
Metabolism

Hepatic metabolism to oxide and hydroxylated metabolites.
Route of elimination Ten to twenty percent of trimethoprim is metabolized, primarily in the liver; the remainder is excreted unchanged in the urine. After oral administration, 50% to 60% of trimethoprim is excreted in the urine within 24 hours, approximately 80% of this being unmetabolized trimethoprim. Trimethoprim also passes the placental barrier and is excreted in human milk.
Half life 8-11 hours in adults with normal renal function
Clearance Not Available
Toxicity LD50=4850 (orally in mice)
Affected organisms
  • Gram negative and gram positive bacteria
Pathways Not Available
Pharmacoeconomics
Manufacturers
  • Monarch pharmaceuticals inc
  • Mutual pharmaceutical co inc
  • Teva pharmaceuticals usa inc
  • Watson laboratories inc
  • Hoffmann la roche inc
  • Fsc laboratories inc
Packagers
Dosage forms
Form Route Strength
Tablet Oral
Prices
Unit description Cost Unit
Bactrim ds tablet 5.53 USD tablet
Bactrim DS 800-160 mg tablet 3.0 USD tablet
Septra DS 800-160 mg tablet 2.43 USD tablet
Septra ds tablet 2.33 USD tablet
Trimethoprim powder 1.79 USD g
Bactrim 400-80 mg tablet 1.63 USD tablet
Septra 80-400 tablet 1.49 USD tablet
Sulfamethoxazole-tmp ds tablet 1.44 USD tablet
Sulfamethoxazole-tmp vial 0.84 USD ml
Trimethoprim 100 mg tablet 0.7 USD tablet
Sulfamethoxazole-Trimethoprim 400-80 mg tablet 0.69 USD tablet
Apo-Trimethoprim 200 mg Tablet 0.55 USD tablet
Primsol 50 mg/5 ml oral soln 0.39 USD ml
Apo-Trimethoprim 100 mg Tablet 0.27 USD tablet
Sulfamethoxazole-tmp ss tablet 0.17 USD tablet
Sulfamethoxazole-Trimethoprim 200-40 mg/5ml Suspension 0.13 USD ml
Sulfatrim 200-40 mg/5ml Suspension 0.13 USD ml
Patents
Country Patent Number Approved Expires
United States 5763449 1996-08-07 2016-08-07
Properties
State solid
Melting point 199 - 203 oC
Experimental Properties
Property Value Source
water solubility 12.1 mg/mL PhysProp
logP 0.6 PhysProp
logS -2.86 [ADME Research, USCD] PhysProp
Predicted Properties
Property Value Source
water solubility 6.15e-01 g/l ALOGPS
logP 1.26 ALOGPS
logP 1.28 ChemAxon Molconvert
logS -2.67 ALOGPS
pKa ChemAxon Molconvert
hydrogen acceptor count 7 ChemAxon Molconvert
hydrogen donor count 2 ChemAxon Molconvert
polar surface area 105.51 ChemAxon Molconvert
rotatable bond count 5 ChemAxon Molconvert
refractivity 81.51 ChemAxon Molconvert
polarizability 29.71 ChemAxon Molconvert
References
Synthesis Reference Not Available
General Reference
  1. Brumfitt W, Hamilton-Miller JM: Reassessment of the rationale for the combinations of sulphonamides with diaminopyrimidines. J Chemother. 1993 Dec;5(6):465-9. Pubmed
  2. Brumfitt W, Hamilton-Miller JM: Limitations of and indications for the use of co-trimoxazole. J Chemother. 1994 Feb;6(1):3-11. Pubmed
  3. Bean DC, Livermore DM, Papa I, Hall LM: Resistance among Escherichia coli to sulphonamides and other antimicrobials now little used in man. J Antimicrob Chemother. 2005 Nov;56(5):962-4. Epub 2005 Sep 8. Pubmed
  4. Felmingham D, Reinert RR, Hirakata Y, Rodloff A: Increasing prevalence of antimicrobial resistance among isolates of Streptococcus pneumoniae from the PROTEKT surveillance study, and compatative in vitro activity of the ketolide, telithromycin. J Antimicrob Chemother. 2002 Sep;50 Suppl S1:25-37. Pubmed
  5. Johnson JR, Manges AR, O’Bryan TT, Riley LW: A disseminated multidrug-resistant clonal group of uropathogenic Escherichia coli in pyelonephritis. Lancet. 2002 Jun 29;359(9325):2249-51. Pubmed
External Links
Resource Link
KEGG Drug D00145 Link_out
KEGG Compound C01965 Link_out
PubChem Compound 5578 Link_out
PubChem Substance 46507125 Link_out
ChemSpider 5376 Link_out
BindingDB 18069 Link_out
ChEBI 9731 Link_out
ChEMBL 9731 Link_out
Therapeutic Targets Database DAP000927 Link_out
PharmGKB PA451788 Link_out
Drug Product Database 2243116 Link_out
RxList http://www.rxlist.com/cgi/generic2/trimeth.htm Link_out
Drugs.com http://www.drugs.com/cdi/trimethoprim.html Link_out
Wikipedia http://en.wikipedia.org/wiki/Trimethoprim Link_out
ATC Codes
  • J01EA01
AHFS Codes
  • 08:36.00
PDB Entries Not Available
FDA label show (98.5 KB)
MSDS show (74.3 KB)
Interactions
Drug Interactions Not Available
Food Interactions
  • Do not take calcium, aluminium, magnesium or iron supplements within 2 hours of taking this medication.
  • Take on empty stomach: 1 hour before or 2 hours after meals.
  • Take with a full glass of water.
Targets

1. Thymidylate synthase

Pharmacological action: yes
Actions: inhibitor
Organism class: human
UniProt ID: P04818 Link_out
Gene: TYMS Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. Pubmed
  2. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. Pubmed
  3. Gamarro F, Yu PL, Zhao J, Edman U, Greene PJ, Santi D: Trypanosoma brucei dihydrofolate reductase-thymidylate synthase: gene isolation and expression and characterization of the enzyme. Mol Biochem Parasitol. 1995 Jun;72(1-2):11-22. Pubmed
  4. Rosowsky A, Papoulis AT, Forsch RA, Queener SF: Synthesis and antiparasitic and antitumor activity of 2, 4-diamino-6-(arylmethyl)-5,6,7,8-tetrahydroquinazoline analogues of piritrexim. J Med Chem. 1999 Mar 25;42(6):1007-17. Pubmed
  5. Reche P, Arrebola R, Santi DV, Gonzalez-Pacanowska D, Ruiz-Perez LM: Expression and characterization of the Trypanosoma cruzi dihydrofolate reductase domain. Mol Biochem Parasitol. 1996 Feb-Mar;76(1-2):175-85. Pubmed
  6. Oefner C, Parisi S, Schulz H, Lociuro S, Dale GE: Inhibitory properties and X-ray crystallographic study of the binding of AR-101, AR-102 and iclaprim in ternary complexes with NADPH and dihydrofolate reductase from Staphylococcus aureus. Acta Crystallogr D Biol Crystallogr. 2009 Aug;65(Pt 8):751-7. Epub 2009 Jul 10. Pubmed
  7. 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

2. Dihydrofolate reductase

Pharmacological action: no
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. Laskowska E, Kuczynska-Wisnik D, Bak M, Lipinska B: Trimethoprim induces heat shock proteins and protein aggregation in E. coli cells. Curr Microbiol. 2003 Oct;47(4):286-9. Pubmed
  2. Floris-Moore MA, Amodio-Groton MI, Catalano MT: Adverse reactions to trimethoprim/sulfamethoxazole in AIDS. Ann Pharmacother. 2003 Dec;37(12):1810-3. Pubmed
  3. Rosowsky A, Fu H, Chan DC, Queener SF: Synthesis of 2,4-diamino-6-[2’-O-(omega-carboxyalkyl)oxydibenz[b,f]azepin-5-yl]methylpt eridines as potent and selective inhibitors of Pneumocystis carinii, Toxoplasma gondii, and Mycobacterium avium dihydrofolate reductase. J Med Chem. 2004 May 6;47(10):2475-85. Pubmed
  4. Nahimana A, Rabodonirina M, Bille J, Francioli P, Hauser PM: Mutations of Pneumocystis jirovecii dihydrofolate reductase associated with failure of prophylaxis. Antimicrob Agents Chemother. 2004 Nov;48(11):4301-5. Pubmed
  5. Barrow EW, Bourne PC, Barrow WW: Functional cloning of Bacillus anthracis dihydrofolate reductase and confirmation of natural resistance to trimethoprim. Antimicrob Agents Chemother. 2004 Dec;48(12):4643-9. Pubmed
  6. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed
Enzymes

1. Cytochrome P450 2C9

Actions: substrate, inhibitor

Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. This enzyme contributes to the wide pharmacokinetics variability of the metabolism of drugs such as S- warfarin, diclofenac, phenytoin, tolbutamide and losartan

UniProt ID: P11712 Link_out
Gene: CYP2C9
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed

2. Cytochrome P450 3A4

Actions: substrate

Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation reactions (e.g. caffeine 8-oxidation, omeprazole sulphoxidation, midazolam 1'-hydroxylation and midazolam 4- hydroxylation) of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. The enzyme also hydroxylates etoposide

UniProt ID: P08684 Link_out
Gene: CYP3A4
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed

3. Cytochrome P450 2C8

Actions: substrate, inhibitor

Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. In the epoxidation of arachidonic acid it generates only 14,15- and 11,12-cis-epoxyeicosatrienoic acids. It is the principal enzyme responsible for the metabolism the anti- cancer drug paclitaxel (taxol)

UniProt ID: P10632 Link_out
Gene: CYP2C8
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of Medicine (2007). Accessed May 28, 2010.
  2. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed
Transporters

1. Multidrug resistance protein 1

Actions: inhibitor, inducer

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. Romiti N, Tramonti G, Chieli E: Influence of different chemicals on MDR-1 P-glycoprotein expression and activity in the HK-2 proximal tubular cell line. Toxicol Appl Pharmacol. 2002 Sep 1;183(2):83-91. Pubmed
  2. Polli JW, Wring SA, Humphreys JE, Huang L, Morgan JB, Webster LO, Serabjit-Singh CS: Rational use of in vitro P-glycoprotein assays in drug discovery. J Pharmacol Exp Ther. 2001 Nov;299(2):620-8. Pubmed
Comments
Drug created on June 13, 2005 07:24 / Updated on November 10, 2010 13:39

This project is supported by Genome Alberta & Genome Canada, a not-for-profit organization that is leading Canada's national genomics strategy with $600 million in funding from the federal government. This project is also supported in part by GenomeQuest, Inc., an enterprise genomic information company serving the life science community.