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Trimethoprim

PubChem CID
5578
Structure
Trimethoprim_small.png
Trimethoprim_3D_Structure.png
Trimethoprim__Crystal_Structure.png
Molecular Formula
Synonyms
  • trimethoprim
  • 738-70-5
  • Proloprim
  • Trimpex
  • Trimetoprim
Molecular Weight
290.32 g/mol
Computed by PubChem 2.2 (PubChem release 2024.11.20)
Dates
  • Create:
    2005-03-25
  • Modify:
    2025-01-18
Description
Trimethoprim is an odorless white powder. Bitter taste. (NTP, 1992)
National Toxicology Program, Institute of Environmental Health Sciences, National Institutes of Health (NTP). 1992. National Toxicology Program Chemical Repository Database. Research Triangle Park, North Carolina.
Trimethoprim is an aminopyrimidine antibiotic whose structure consists of pyrimidine 2,4-diamine and 1,2,3-trimethoxybenzene moieties linked by a methylene bridge. It has a role as an EC 1.5.1.3 (dihydrofolate reductase) inhibitor, a xenobiotic, an environmental contaminant, a drug allergen, an antibacterial drug and a diuretic. It is a member of methoxybenzenes and an aminopyrimidine.
Trimethoprim is an antifolate antibacterial agent that inhibits bacterial dihydrofolate reductase (DHFR), a critical enzyme that catalyzes the formation of tetrahydrofolic acid (THF) - in doing so, it prevents the synthesis of bacterial DNA and ultimately continued bacterial survival. Trimethoprim is often used in combination with [sulfamethoxazole] due to their complementary and synergistic mechanisms but may be used as a monotherapy in the treatment and/or prophylaxis of urinary tract infections. It is structurally and chemically related to [pyrimethamine], another antifolate antimicrobial used in the treatment of plasmodial infections.
See also: Sulfamethoxazole; Trimethoprim (component of); Trimethoprim sulfate (has salt form); Trimethoprim Hydrochloride (has salt form) ... View More ...

1 Structures

1.1 2D Structure

Chemical Structure Depiction
Trimethoprim.png

1.2 3D Conformer

1.3 Crystal Structures

1 of 4
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CCDC Number
Crystal Structure Data
Crystal Structure Depiction
Crystal Structure Depiction

2 Names and Identifiers

2.1 Computed Descriptors

2.1.1 IUPAC Name

5-[(3,4,5-trimethoxyphenyl)methyl]pyrimidine-2,4-diamine
Computed by Lexichem TK 2.7.0 (PubChem release 2024.11.20)

2.1.2 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)
Computed by InChI 1.07.0 (PubChem release 2024.11.20)

2.1.3 InChIKey

IEDVJHCEMCRBQM-UHFFFAOYSA-N
Computed by InChI 1.07.0 (PubChem release 2024.11.20)

2.1.4 SMILES

COC1=CC(=CC(=C1OC)OC)CC2=CN=C(N=C2N)N
Computed by OEChem 2.3.0 (PubChem release 2024.12.12)

2.2 Molecular Formula

C14H18N4O3
Computed by PubChem 2.2 (PubChem release 2024.11.20)

2.3 Other Identifiers

2.3.1 CAS

738-70-5

2.3.2 European Community (EC) Number

2.3.3 UNII

2.3.4 UN Number

2.3.5 ChEBI ID

2.3.6 ChEMBL ID

2.3.7 DrugBank ID

2.3.8 DSSTox Substance ID

2.3.9 HMDB ID

2.3.10 KEGG ID

2.3.11 Metabolomics Workbench ID

2.3.12 NCI Thesaurus Code

2.3.13 Nikkaji Number

2.3.14 NSC Number

2.3.15 PharmGKB ID

2.3.16 Pharos Ligand ID

2.3.17 RXCUI

2.3.18 Wikidata

2.3.19 Wikipedia

2.4 Synonyms

2.4.1 MeSH Entry Terms

  • Proloprim
  • Trimethoprim
  • Trimpex

2.4.2 Depositor-Supplied Synonyms

3 Chemical and Physical Properties

3.1 Computed Properties

Property Name
Molecular Weight
Property Value
290.32 g/mol
Reference
Computed by PubChem 2.2 (PubChem release 2024.11.20)
Property Name
XLogP3
Property Value
0.9
Reference
Computed by XLogP3 3.0 (PubChem release 2024.11.20)
Property Name
Hydrogen Bond Donor Count
Property Value
2
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2024.11.20)
Property Name
Hydrogen Bond Acceptor Count
Property Value
7
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2024.11.20)
Property Name
Rotatable Bond Count
Property Value
5
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2024.11.20)
Property Name
Exact Mass
Property Value
290.13789045 Da
Reference
Computed by PubChem 2.2 (PubChem release 2024.11.20)
Property Name
Monoisotopic Mass
Property Value
290.13789045 Da
Reference
Computed by PubChem 2.2 (PubChem release 2024.11.20)
Property Name
Topological Polar Surface Area
Property Value
106 Ų
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2024.11.20)
Property Name
Heavy Atom Count
Property Value
21
Reference
Computed by PubChem
Property Name
Formal Charge
Property Value
0
Reference
Computed by PubChem
Property Name
Complexity
Property Value
307
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2024.11.20)
Property Name
Isotope Atom Count
Property Value
0
Reference
Computed by PubChem
Property Name
Defined Atom Stereocenter Count
Property Value
0
Reference
Computed by PubChem
Property Name
Undefined Atom Stereocenter Count
Property Value
0
Reference
Computed by PubChem
Property Name
Defined Bond Stereocenter Count
Property Value
0
Reference
Computed by PubChem
Property Name
Undefined Bond Stereocenter Count
Property Value
0
Reference
Computed by PubChem
Property Name
Covalently-Bonded Unit Count
Property Value
1
Reference
Computed by PubChem
Property Name
Compound Is Canonicalized
Property Value
Yes
Reference
Computed by PubChem (release 2021.10.14)

3.2 Experimental Properties

3.2.1 Physical Description

Trimethoprim is an odorless white powder. Bitter taste. (NTP, 1992)
National Toxicology Program, Institute of Environmental Health Sciences, National Institutes of Health (NTP). 1992. National Toxicology Program Chemical Repository Database. Research Triangle Park, North Carolina.
Solid

3.2.2 Color / Form

White to cream, crystalline powder
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. 13th Edition, Whitehouse Station, NJ: Merck and Co., Inc., 2001., p. 1730

3.2.3 Odor

Odorless
McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 92. Bethesda, MD: American Society of Hospital Pharmacists, Inc., 1992 (Plus Supplements 1992)., p. 453

3.2.4 Taste

Bitter
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. 13th Edition, Whitehouse Station, NJ: Merck and Co., Inc., 2001., p. 1730

3.2.5 Melting Point

390 to 397 °F (NTP, 1992)
National Toxicology Program, Institute of Environmental Health Sciences, National Institutes of Health (NTP). 1992. National Toxicology Program Chemical Repository Database. Research Triangle Park, North Carolina.
199-203 °C
PhysProp
199 - 203 °C

3.2.6 Solubility

less than 1 mg/mL at 75 °F (NTP, 1992)
National Toxicology Program, Institute of Environmental Health Sciences, National Institutes of Health (NTP). 1992. National Toxicology Program Chemical Repository Database. Research Triangle Park, North Carolina.
400 mg/L (at 25 °C)
YALKOWSKY,SH & DANNENFELSER,RM (1992)
... Very slightly soluble in water and slightly soluble in alcohol.
McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 92. Bethesda, MD: American Society of Hospital Pharmacists, Inc., 1992 (Plus Supplements 1992)., p. 453
Soluble in N,N-dimethylacetamide (DMAC) at 13.86; benzyl alcohol at 7.29; propylene glycol at 2.57; chloroform at 1.82; methanol at 1.21; ether at 0.003; benzene at 0.002 g/100 ml at 25 °C.
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. 13th Edition, Whitehouse Station, NJ: Merck and Co., Inc., 2001., p. 1730
In water, 400 mg/l @ 25 °C
Yalkowsky SH, Dannenfelser RM; The AQUASOL dATAbASE of Aqueous Solubility. Ver 5. Tucson, AZ: Univ AZ, College of Pharmacy (1992)
6.15e-01 g/L

3.2.7 LogP

0.91
HANSCH,C ET AL. (1995)
log Kow = 0.91
Hansch, C., Leo, A., D. Hoekman. Exploring QSAR - Hydrophobic, Electronic, and Steric Constants. Washington, DC: American Chemical Society., 1995., p. 124
0.6

3.2.8 LogS

-2.86
ADME Research, USCD

3.2.9 Stability / Shelf Life

The solubility of trimethoprim in aqueous solns is partially dependent on the pH of the soln. Trimethoprim is a weak base, & its solubility is lower in solns with a more alkaline pH.
Trissel, L.A. Handbook on Injectable Drugs. 9th ed. Bethesda, MD. American Society of Health-System Pharmacists' Product Development. 1996., p. 1063
The stability of admixtures of sulfamethoxazole (I) & trimethoprim (II) at various concns in 5% dextrose (III) injection & 0.9% sodium chloride (IV) injection was studied at 0, 0.5, 1, 2, 4, 8, 14, 24, & 48 hr; appropriate volumes of a formulation containing 400 mg of I & 80 mg of II/5 ml were mixed with III or IV injection to provide dilutions of 1:25 v/v, 1:20 v/v, 1:15 v/v, & 1:10 v/v. Stability studies by pH determinations, HPLC assays, & visual inspections for precipitate showed that I was stable in all admixtures during the study period, whereas the stability of II was dependent on concn & vehicle. Trimethoprim was more stable in III injection & stability decreased with increasing concns. It is suggested that concentrated solns of I-II be prepared in 5% III injection, infused within 1 hr of preparation, & visually inspected for precipitation before & during infusion.
Jarosinki PF, et al; Am. J. Hosp. Pharm. 46 (Apr): 732-737 (1989)

3.2.10 Decomposition

When heated to decomposition it emits toxic fumes of /nitrogen oxide/.
Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996., p. 3280

3.2.11 Dissociation Constants

pKa
7.12 (at 20 °C)
PERRIN,DD (1972)
pKa= 7.12 (conjugate acid)
Perrin DD; Dissociation Constants of Organic Bases in Aqueous Solution. London, UK: Butterworth (1965)

3.2.12 Collision Cross Section

170.8 Ų [M+H]+ [CCS Type: TW; Method: Major Mix IMS/Tof Calibration Kit (Waters)]

169.82 Ų [M+Na]+ [CCS Type: TW; Method: calibrated with polyalanine and drug standards]

165.75 Ų [M+K]+ [CCS Type: TW; Method: calibrated with polyalanine and drug standards]

169.64 Ų [M+H]+ [CCS Type: TW; Method: calibrated with polyalanine and drug standards]

158.24 Ų [M+H-H2O]+ [CCS Type: TW; Method: calibrated with polyalanine and drug standards]

Ross et al. JASMS 2022; 33; 1061-1072. DOI:10.1021/jasms.2c00111
171.2 Ų [M+H]+ [CCS Type: TW; Method: calibrated with polyalanine and drug standards]

172.89 Ų [M+H]+

187.42 Ų [M+Na]+

S61 | UJICCSLIB | Collision Cross Section (CCS) Library from UJI | DOI:10.5281/zenodo.3549476

3.2.13 Kovats Retention Index

Standard non-polar
2564 , 2574 , 2564.7
Semi-standard non-polar
2605.9 , 2582.4 , 2598.4

3.3 Chemical Classes

Pharmaceutical

3.3.1 Drugs

Pharmaceuticals -> unsed in Switzerland 2014-2016
S113 | SWISSPHARMA24 | 2024 Swiss Pharmaceutical List with Metabolites | DOI:10.5281/zenodo.10501043
Pharmaceuticals
S10 | SWISSPHARMA | Pharmaceutical List with Consumption Data | DOI:10.5281/zenodo.2623484
Pharmaceuticals -> Listed in ZINC15
S55 | ZINC15PHARMA | Pharmaceuticals from ZINC15 | DOI:10.5281/zenodo.3247749
Pharmaceuticals -> Antibiotics (Bacteriostatic)
S56 | UOATARGPHARMA | Target Pharmaceutical/Drug List from University of Athens | DOI:10.5281/zenodo.3248837
Pharmaceuticals -> Antibiotics
S6 | ITNANTIBIOTIC | Antibiotic List from the ITN MSCA ANSWER | DOI:10.5281/zenodo.2621956
3.3.1.1 Human Drugs
Breast Feeding; Lactation; Milk, Human; Anti-Infective Agents, Urinary; Antibacterial Agents; Folic Acid Antagonists
Human drug -> Discontinued
Human drug -> Prescription; Discontinued; Active ingredient (TRIMETHOPRIM)
Access group antibiotics
3.3.1.2 Animal Drugs
Active Ingredients (Trimethoprim) -> FDA Greenbook
Pharmaceuticals -> Animal Drugs -> Approved in Taiwan
S72 | NTUPHTW | Pharmaceutically Active Substances from National Taiwan University | DOI:10.5281/zenodo.3955664
Pharmaceuticals -> UK Veterinary Medicines Directorate List
S104 | UKVETMED | UK Veterinary Medicines Directorate's List | DOI:10.5281/zenodo.7802119

4 Spectral Information

4.1 1D NMR Spectra

4.1.1 13C NMR Spectra

1 of 2
Instrument Name
Jeol GX-270
Copyright
Copyright © 2002-2024 Wiley-VCH Verlag GmbH & Co. KGaA. All Rights Reserved.
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2 of 2
Instrument Name
see comment
Copyright
Copyright © 2002-2024 Wiley-VCH Verlag GmbH & Co. KGaA. All Rights Reserved.
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4.1.2 15N NMR Spectra

1 of 2
Copyright
Copyright © 2016-2024 W. Robien, Inst. of Org. Chem., Univ. of Vienna. All Rights Reserved.
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2 of 2
Copyright
Copyright © 2016-2024 W. Robien, Inst. of Org. Chem., Univ. of Vienna. All Rights Reserved.
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4.2 Mass Spectrometry

4.2.1 GC-MS

1 of 10
View All
Spectra ID
Instrument Type
EI-B
Ionization Mode
positive
Top 5 Peaks

290.0 99.99

259.0 25.91

275.0 22.41

43.0 21.09

28.0 19.20

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Notes
instrument=HITACHI M-80
2 of 10
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MoNA ID
MS Category
Experimental
MS Type
GC-MS
MS Level
MS1
Instrument
HITACHI M-80
Instrument Type
EI-B
Ionization Mode
positive
Top 5 Peaks

290 99.99

259 25.91

275 22.41

43 21.09

28 19.20

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License
CC BY-NC-SA

4.2.2 MS-MS

1 of 9
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Spectra ID
Ionization Mode
Positive
Top 5 Peaks

123.0666 100

81.0448 47.43

229.1085 33.04

233.1034 26.72

232.0956 26.36

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2 of 9
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Spectra ID
Ionization Mode
Positive
Top 5 Peaks

230.1166 100

123.0667 63.80

261.0985 44.31

258.1113 38.99

275.1141 24.62

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4.2.3 LC-MS

1 of 62
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Authors
ACESx, Jonathan W. Martin Group
Instrument
QExactive Orbitrap HF-X (Thermo Scientific)
Instrument Type
LC-ESI-QFT
MS Level
MS2
Ionization Mode
POSITIVE
Ionization
ESI
Collision Energy
Ramp 20%-70% (nominal)
Fragmentation Mode
HCD
Column Name
Waters; Acquity UPLC BEH C18, 2.1 x 100 mm, 1.7 um, Waters
Retention Time
9.6574
Top 5 Peaks

291.14633 999

123.06696 146

261.099 72

229.10901 71

257.10446 62

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License
CC BY
2 of 62
View All
Authors
ACESx, Jonathan W. Martin Group
Instrument
QExactive Orbitrap HF-X (Thermo Scientific)
Instrument Type
LC-ESI-QFT
MS Level
MS2
Ionization Mode
NEGATIVE
Ionization
ESI
Collision Energy
Ramp 20%-70% (nominal)
Fragmentation Mode
HCD
Column Name
Waters; Acquity UPLC BEH C18, 2.1 x 100 mm, 1.7 um, Waters
Retention Time
9.5858
Precursor m/z
289.131
Top 5 Peaks

289.13138 999

227.05772 442

274.10693 252

243.05194 136

198.0545 62

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License
CC BY

4.2.4 Other MS

1 of 4
View All
Authors
ACESx, Jonathan W. Martin Group
Instrument
QExactive Orbitrap HF-X (Thermo Scientific)
Instrument Type
LC-APCI-QFT
MS Level
MS2
Ionization Mode
POSITIVE
Ionization
APCI
Collision Energy
Ramp 20%-70% (nominal)
Fragmentation Mode
HCD
Column Name
Waters; Acquity UPLC BEH C18, 2.1 x 100 mm, 1.7 um, Waters
Retention Time
9.5878
Precursor m/z
291.1452
Top 5 Peaks

291.14627 999

123.06676 183

261.09897 59

81.04478 58

257.10388 52

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License
CC BY
2 of 4
View All
Authors
NARA WOMEN'S UNIVERSITY
Instrument
HITACHI M-80
Instrument Type
EI-B
MS Level
MS
Ionization Mode
POSITIVE
Ionization
ENERGY 70 eV
Top 5 Peaks

290 999

259 259

275 224

43 211

28 192

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License
CC BY-NC-SA

4.3 UV Spectra

4.3.1 UV-VIS Spectra

1 of 2
Copyright
Copyright © 2008-2024 John Wiley & Sons, Inc. All Rights Reserved.
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2 of 2
Copyright
Copyright © 2008-2024 John Wiley & Sons, Inc. All Rights Reserved.
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4.4 IR Spectra

4.4.1 FTIR Spectra

Technique
KBr WAFER
Source of Sample
A. BROSSI, HOFFMANN-LA ROCHE INC., NUTLEY, NEW JERSEY
Copyright
Copyright © 1980, 1981-2024 John Wiley & Sons, Inc. All Rights Reserved.
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4.4.2 ATR-IR Spectra

Instrument Name
Bio-Rad FTS
Technique
ATR-Neat (DuraSamplIR II) ground
Source of Spectrum
Forensic Spectral Research
Source of Sample
Fluka Vetranal, Sigma-Aldrich Inc.
Catalog Number
46984
Lot Number
7271X
Copyright
Copyright © 2009-2024 John Wiley & Sons, Inc. All Rights Reserved.
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6 Chemical Vendors

7 Drug and Medication Information

7.1 Drug Indication

As a monotherapy, trimethoprim is indicated for the treatment of acute episodes of uncomplicated urinary tract infections caused by susceptible bacteria, including _E. coli._, _K. pneumoniae_, _Enterobacter spp._, _P. mirabilis_, and coagulase-negative _Staphylococcus_ species. In various formulations in combination with [sulfamethoxazole], trimethoprim is indicated for the following infections caused by bacteria with documented susceptibility: urinary tract infections, acute otitis media in pediatric patients (when clinically indicated), acute exacerbations of chronic bronchitis in adults, enteritis caused by susceptible _Shigella_, prophylaxis and treatment of _Pneumocystis jiroveci_ pneumonia, and travelers' diarrhea caused by enterotoxigenic _E. coli_. Trimethoprim is available as an ophthalmic solution in combination with [polymyxin B] for the treatment of acute bacterial conjunctivitis, blepharitis, and blepharoconjunctivitis caused by susceptible bacteria.

7.2 Drug Classes

Breast Feeding; Lactation; Milk, Human; Anti-Infective Agents, Urinary; Antibacterial Agents; Folic Acid Antagonists

7.3 WHO Essential Medicines

Drug
Drug Classes
Access group antibiotics
Formulation
(1) Oral - Liquid: 50 mg per mL; (2) Oral - Solid: 100 mg; 200 mg
Indication
Infectious cystitis

7.4 FDA Approved Drugs

7.5 FDA Orange Book

7.6 FDA National Drug Code Directory

7.7 FDA Green Book

7.8 Drug Labels

Drug and label
Active ingredient and drug

7.9 Clinical Trials

7.9.1 ClinicalTrials.gov

7.9.2 EU Clinical Trials Register

7.9.3 NIPH Clinical Trials Search of Japan

7.10 Therapeutic Uses

Anti-Infective Agents, Urinary; Antimalarials; Antimetabolites; Folic Acid Antagonists
National Library of Medicine's Medical Subject Headings online file (MeSH, 1999)
Trimethoprim given alone has also been effective for urinary tract infections, but the development of resistant organisms limits the usefulness of this treatment.
Gilman, A.G., T.W. Rall, A.S. Nies and P. Taylor (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 8th ed. New York, NY. Pergamon Press, 1990., p. 1056
Trimethoprim is indicated in the treatment of initial, uncomplicated urinary tract infections caused by susceptible strains of Escherichia coli, Proteus mirabilis, Klebsiella pneumoniae, Enterobacter species, & coagulase-negative Staphylococcus species, including Staphylococcus saprophyticus. /Included in US product labeling/
MICROMEDEX Thomson Health Care. USPDI - Drug Information for the Health Care Professional. 22nd ed. Volume 1. MICROMEDEX Thomson Health Care, Greenwood Village, CO. 2002. Content Reviewed and Approved by the U.S. Pharmacopeial Convention, Inc., p. 2848
trimethoprim is used in the prophylaxis of bacterial urinary tract infections. /NOT included in US product labeling/
MICROMEDEX Thomson Health Care. USPDI - Drug Information for the Health Care Professional. 22nd ed. Volume 1. MICROMEDEX Thomson Health Care, Greenwood Village, CO. 2002. Content Reviewed and Approved by the U.S. Pharmacopeial Convention, Inc., p. 2848
For more Therapeutic Uses (Complete) data for TRIMETHOPRIM (8 total), please visit the HSDB record page.

7.11 Drug Warnings

Because trimethoprim may interfere with folic acid metabolism, the drug should be used with caution in nursing women.
McEvoy, G.K. (ed.). American Hospital Formulary Service- Drug Information 2002. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2002 (Plus Supplements)., p. 842
Adverse GI reactions occur in approximately 6% of patients receiving trimethoprim and may include epigastric discomfort, nausea, vomiting, glossitis, and abnormal taste sensation. Elevations in serum aminotransferase (transaminase) and bilirubin concentrations have been reported in patients receiving the drug, but the clinical importance of these findings is not known. Cholestatic jaundice has been reported rarely.
McEvoy, G.K. (ed.). American Hospital Formulary Service- Drug Information 2002. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2002 (Plus Supplements)., p. 842
The most frequent adverse effects of trimethoprim are rash and pruritus. Mild to moderate rashes appearing 7-14 days after initiation of trimethoprim therapy reportedly occur in 2.9-6.7% of patients receiving 200 mg of the drug daily. Rashes are generally maculopapular, morbilliform, and pruritic. Rashes have been reported to occur in up to 24% of patients receiving 400 mg or more trimethoprim for 14 days. Photosensitivity (e.g., erythematous phototoxic eruptions with subsequent hyperpigmentation of sun-exposed skin) also has occurred. Exfoliative dermatitis, toxic epidermal necrolysis (Lyell's syndrome), erythema multiforme, and Stevens-Johnson syndrome have been reported rarely in patients receiving the drug. Anaphylaxis also has occurred rarely.
McEvoy, G.K. (ed.). American Hospital Formulary Service- Drug Information 2002. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2002 (Plus Supplements)., p. 842
Safety and efficacy of trimethoprim in infants younger than 2 months of age and efficacy of the drug when used as single agent in children younger than 12 years of age have not been established. Trimethoprim should be used with caution in children who have the fragile X chromosome associated with mental retardation, because folate depletion may worsen the psychomotor regression associated with the disorder.
McEvoy, G.K. (ed.). American Hospital Formulary Service- Drug Information 2002. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2002 (Plus Supplements)., p. 842
For more Drug Warnings (Complete) data for TRIMETHOPRIM (28 total), please visit the HSDB record page.

7.12 Drug Tolerance

Most gram-negative and gram-positive microorganisms are sensitive to trimethoprim, but resistance can develop when the drug is used alone.
Hardman, J.G., L.E. Limbird, P.B. Molinoff, R.W. Ruddon, A.G. Goodman (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 9th ed. New York, NY: McGraw-Hill, 1996., p. 1177
Bacterial resistance to trimethoprim-sulfamethoxazole is a rapidly increasing problem, although resistance is lower than it is to either of the agents alone. Resistance often is due to the acquisition of a plasmid that codes for an altered dihydrofolate reductase. The development of resistance is a problem for treatment of many different bacterial infections.
Hardman, J.G., L.E. Limbird, P.B. Molinoff, R.W. Ruddon, A.G. Goodman (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 9th ed. New York, NY: McGraw-Hill, 1996., p. 1177

8 Pharmacology and Biochemistry

8.1 Pharmacodynamics

Trimethoprim exerts its antimicrobial effects by inhibiting an essential step in the synthesis of bacterial nucleic acids and proteins. It has shown activity against several species of gram-negative bacteria, as well as coagulase-negative _Staphylococcus_ species. Resistance to trimethoprim may arise via a variety of mechanisms, including alterations to the bacterial cell wall, overproduction of dihydrofolate reductase, or production of resistant dihydrofolate reductase. Rarely, trimethoprim can precipitate the development of blood disorders (e.g. thrombocytopenia, leukopenia, etc.) which may be preceded by symptoms such as sore throat, fever, pallor, and or purpura - patients should be monitored closely for the development of these symptoms throught the course of therapy. As antimicrobial susceptibility patterns are geographically distinct, local antibiograms should be consulted to ensure adequate coverage of relevant pathogens prior to use.

8.2 MeSH Pharmacological Classification

Cytochrome P-450 CYP2C8 Inhibitors
Drugs and compounds which inhibit or antagonize the biosynthesis or actions of CYTOCHROME P-450 CYP2C8. (See all compounds classified as Cytochrome P-450 CYP2C8 Inhibitors.)
Anti-Dyskinesia Agents
Drugs used in the treatment of movement disorders. Most of these act centrally on dopaminergic or cholinergic systems. Among the most important clinically are those used for the treatment of Parkinson disease (ANTIPARKINSON AGENTS) and those for the tardive dyskinesias. (See all compounds classified as Anti-Dyskinesia Agents.)
Antimalarials
Agents used in the treatment of malaria. They are usually classified on the basis of their action against plasmodia at different stages in their life cycle in the human. (From AMA, Drug Evaluations Annual, 1992, p1585) (See all compounds classified as Antimalarials.)
Anti-Infective Agents, Urinary
Substances capable of killing agents causing urinary tract infections or of preventing them from spreading. (See all compounds classified as Anti-Infective Agents, Urinary.)
Folic Acid Antagonists
Inhibitors of the enzyme, dihydrofolate reductase (TETRAHYDROFOLATE DEHYDROGENASE), which converts dihydrofolate (FH2) to tetrahydrofolate (FH4). They are frequently used in cancer chemotherapy. (From AMA, Drug Evaluations Annual, 1994, p2033) (See all compounds classified as Folic Acid Antagonists.)

8.3 FDA Pharmacological Classification

1 of 2
FDA UNII
AN164J8Y0X
Active Moiety
TRIMETHOPRIM
Pharmacological Classes
Established Pharmacologic Class [EPC] - Dihydrofolate Reductase Inhibitor Antibacterial
Pharmacological Classes
Mechanisms of Action [MoA] - Dihydrofolate Reductase Inhibitors
Pharmacological Classes
Mechanisms of Action [MoA] - Cytochrome P450 2C8 Inhibitors
Pharmacological Classes
Mechanisms of Action [MoA] - Organic Cation Transporter 2 Inhibitors
FDA Pharmacology Summary
Trimethoprim is a Dihydrofolate Reductase Inhibitor Antibacterial. The mechanism of action of trimethoprim is as a Dihydrofolate Reductase Inhibitor, and Cytochrome P450 2C8 Inhibitor, and Organic Cation Transporter 2 Inhibitor.
2 of 2
Non-Proprietary Name
TRIMETHOPRIM
Pharmacological Classes
Organic Cation Transporter 2 Inhibitors [MoA]; Dihydrofolate Reductase Inhibitor Antibacterial [EPC]; Dihydrofolate Reductase Inhibitors [MoA]; Cytochrome P450 2C8 Inhibitors [MoA]

8.4 ATC Code

S76 | LUXPHARMA | Pharmaceuticals Marketed in Luxembourg | Pharmaceuticals marketed in Luxembourg, as published by d'Gesondheetskeess (CNS, la caisse nationale de sante, www.cns.lu), mapped by name to structures using CompTox by R. Singh et al. (in prep.). List downloaded from https://cns.public.lu/en/legislations/textes-coordonnes/liste-med-comm.html. Dataset DOI:10.5281/zenodo.4587355

J - Antiinfectives for systemic use

J01 - Antibacterials for systemic use

J01E - Sulfonamides and trimethoprim

J01EA - Trimethoprim and derivatives

J01EA01 - Trimethoprim

J01EA01

8.5 Absorption, Distribution and Excretion

Absorption
Steady-state concentrations are achieved after approximately 3 days of repeat administration. Average peak serum concentrations of approximately 1 µg/mL (Cmax) are achieved within 1 to 4 hours (Tmax) following the administration of a single 100mg dose. Trimethoprim appears to follow first-order pharmacokinetics, as a single 200mg dose results in serum concentrations approximately double that of a 100mg dose. The steady-state AUC of orally administered trimethoprim is approximately 30 mg/L·h.
Route of Elimination
Approximately 10-20% of an ingested trimethoprim dose is metabolized, primarily in the liver, while a large portion of the remainder is excreted unchanged in the urine. Following oral administration, 50% to 60% of trimethoprim is excreted in the urine within 24 hours, approximately 80% of which is unchanged parent drug.
Volume of Distribution
Trimethoprim is extensively distributed into various tissues following oral administration. It distributes well into sputum, middle ear fluid, and bronchial secretions. Trimethoprim distributes efficiently into vaginal fluids, with observed concentrations approximately 1.6-fold higher than those seen in the serum. It may pass the placental barrier and into breast milk. Trimethoprim is also sufficiently excreted in the feces to markedly reduce and/or eliminate trimethoprim-susceptible fecal flora.
Clearance
Following oral administration, the renal clearance of trimethoprim has been variably reported between 51.7 - 91.3 mL/min.
Trimethoprim is widely distributed into body tissues & fluids including the aqueous humor, middle ear fluid, saliva, lung tissue, sputum, seminal fluid, prostatic tissue & fluid, vaginal secretions, bile, bone, & /cerebrospinal fluid/. The apparent volume of distribution of trimethoprim in adults with normal renal function ranges from 100-120 l. ... Trimethoprim is 42-46% bound to plasma proteins. Trimethoprim readily crosses the placenta, & amniotic fluid concns are reported to be 80% of concurrent maternal serum concns.
McEvoy, G.K. (ed.). American Hospital Formulary Service- Drug Information 2002. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2002 (Plus Supplements)., p. 843
Only small amounts of trimethoprim are excreted in feces via biliary elimination. Trimethoprim may be moderately removed by hemodialysis.
McEvoy, G.K. (ed.). American Hospital Formulary Service- Drug Information 2002. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2002 (Plus Supplements)., p. 844
Trimethoprim is readily & almost completely absorbed from the GI tract. Peak serum concns of approx 1, 1.6, & 2 ug/ml are reached in 1-4 hr after single 100-, 160-, & 200 mg oral doses of trimethoprim. Following multiple-dose oral admin, steady-state peak serum concns of trimethoprim usually are 50% greater than those obtained after single-dose admin of the drug. Steady-state serum concns range from 1.2-3.2 ug/ml following oral admin of 160 mg of trimethoprim every 12 hr in adults with renal function.
McEvoy, G.K. (ed.). American Hospital Formulary Service- Drug Information 2002. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2002 (Plus Supplements)., p. 843
Rapidly and widely distributed to various tissues and fluids, including kidneys, liver, spleen, bronchial secretions, saliva, and seminal fluid. Trimethoprim has also been demonstrated in bile; aqueous humor; bone marrow and spongy, but not compact, bone.
MICROMEDEX Thomson Health Care. USPDI - Drug Information for the Health Care Professional. 22nd ed. Volume 1. MICROMEDEX Thomson Health Care, Greenwood Village, CO. 2002. Content Reviewed and Approved by the U.S. Pharmacopeial Convention, Inc., p. 2849
For more Absorption, Distribution and Excretion (Complete) data for TRIMETHOPRIM (12 total), please visit the HSDB record page.

8.6 Metabolism / Metabolites

Trimethoprim undergoes oxidative metabolism to a number of metabolites, the most abundant of which are the demethylated 3'- and 4'- metabolites, accounting for approximately 65% and 25% of the total metabolite formation, respectively. Minor products include N-oxide metabolites (<5%) and benzylic metabolites in even smaller quantities. The parent drug is considered to be the therapeutically active form. The majority of trimethoprim biotransformation appears to involve CYP2C9 and CYP3A4 enzymes, with CYP1A2 contributing to a lesser extent.
Trimethoprim is metabolized in the liver to oxide and hydroxylated metabolites ... .
McEvoy, G.K. (ed.). American Hospital Formulary Service- Drug Information 2002. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2002 (Plus Supplements)., p. 844
The pharmacokinetics were studied of sulfadimethoxine (SDM) or sulfamethoxazole (SMX) in combination with trimethoprim (TMP) administered as a single oral dose (25 mg + 5 mg/kg bw) to 2 groups of 6 healthy pigs. The elimination half-lives of SMX & TMP were quite similar (2-3 hr); SDM had a relatively long half-life of 13 hr. Both sulfonamides (S) were exclusively metabolized to N4-acetyl derivatives but to different extents. The main metabolic pathway for TMP was O-demethylation & subsequent conjugation. In addition, the plasma concns of these drugs & their main metabolites after medication with different in-feed concns were determined. The drug (S:TMP) concns in the feed were 250:50, 500:100, & 1000:200 mg/kg. Steady-state concns were achieved within 48 hr of feed medication, twice daily (SDM+TMP) or 3 times/day (SMX+TMP). Protein binding of SDM & its metabolite was high (>93%), whereas SMX, TMP & their metabolites showed moderate binding (48-75%). Feed medication with 500 ppm sulfonamide combined with 100 ppm TMP provided minimum steady-state plasma concns (C(ss,min)) higher than the concn required for inhibition of the growth of 90% of Actinobacillus pleuropneumoniae strains (n=20).
Mengelers MF, et al; Vet Res Commun 25 (6): 461-481. 2001.

8.7 Biological Half-Life

Trimethoprim half-life ranges from 8-10 hours, but may be prolonged in patients with renal dysfunction.
Trimethoprim has a serum half-life of approx 8-11 hr in adults with normal renal function. In adults with creatinine clearances of 10-30 or 0-10 ml/min, serum half-life of the drug may incr to 15 hr or >26 hr, respectively. Trimethoprim serum half-lives of about 7.7 & 5.5 hr have been reported in children <1 yr of age & between 1 & 10 yr of age, respectively.
McEvoy, G.K. (ed.). American Hospital Formulary Service- Drug Information 2002. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2002 (Plus Supplements)., p. 843

8.8 Mechanism of Action

Trimethoprim is a reversible inhibitor of dihydrofolate reductase, one of the principal enzymes catalyzing the formation of tetrahydrofolic acid (THF) from dihydrofolic acid (DHF). Tetrahydrofolic acid is necessary for the biosynthesis of bacterial nucleic acids and proteins and ultimately for continued bacterial survival - inhibiting its synthesis, then, results in bactericidal activity. Trimethoprim binds with a much stronger affinity to bacterial dihydrofolate reductase as compared to its mammalian counterpart, allowing trimethoprim to selectively interfere with bacterial biosynthetic processes. Trimethoprim is often given in combination with sulfamethoxazole, which inhibits the preceding step in bacterial protein synthesis - given together, sulfamethoxazole and trimethoprim inhibit two consecutive steps in the biosynthesis of bacterial nucleic acids and proteins. As a monotherapy trimethoprim is considered bacteriostatic, but in combination with sulfamethoxazole is thought to exert bactericidal activity.
Trimethoprim is a bacteriostatic lipophilic weak base structurally related to pyrimethamine. It binds to and reversibly inhibits the bacterial enzyme dihydrofolate reductase, selectively blocking conversion of dihydrofolic acid to its functional form, tetrahydrofolic acid. This depletes folate, an essential cofactor in the biosynthesis of nucleic acids, resulting in interference with bacterial nucleic acid and protein production. Bacterial dihydrofolate reductase is approximately 50,000 to 60,000 times more tightly bound by trimethoprim than is the corresponding mammalian enzyme.
US Pharmacopeial Convention; US Pharmacopeia Dispensing Information (USP DI); Drug Information for the Health Care Professional 12th ed, V.IB p.2531 (1992)
To determine the incidence & severity of hyperkalemia during trimethoprim therapy, 30 consecutive patients with acquired immunodeficiency syndrome receiving high-dose (20 mg/kg/day) trimethoprim were studied; in addition, the mechanism of trimethoprim-induced hyperkalemia was investigated in rats. Trimethoprim increased serum potassium concn by 0.6 mmol/l despite normal adrenocortical function & glomerular filtration rate. Serum potassium levels >5 mmol/l were observed during trimethoprim treatment in 15 of 30 patients. In rats, iv trimethoprim inhibited renal potassium excretion by 40% & increased sodium excretion by 46%. It was concluded that trimethoprim blocks apical membrane sodium channels in the mammalian distal nephron. As a consequence, the transepithelial voltage is reduced & potassium secretion is inhibited. Decreased renal potassium excretion secondary to these direct effects on kidney tubules leads to hyperkalemia in a substantial number of patients being treated with trimethoprim-containing drugs.
Velazquez H, et al; Ann. Intern. Med. 119 (Aug 15): 296-301 (1993)

8.9 Human Metabolite Information

8.9.1 Cellular Locations

Membrane

9 Use and Manufacturing

9.1 Uses

EPA CPDat Chemical and Product Categories
The Chemical and Products Database, a resource for exposure-relevant data on chemicals in consumer products, Scientific Data, volume 5, Article number: 180125 (2018), DOI:10.1038/sdata.2018.125
Veterinary antimicrobial agent
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. 13th Edition, Whitehouse Station, NJ: Merck and Co., Inc., 2001., p. 1730
Has a broad spectrum of antimicrobial activity and extends the spectrum of sulfamethoxazole to include many urinary and systemic pathogens untreatable by this sulfa drug alone.
Gerhartz, W. (exec ed.). Ullmann's Encyclopedia of Industrial Chemistry. 5th ed.Vol A1: Deerfield Beach, FL: VCH Publishers, 1985 to Present., p. VA6 (1986) 189
MEDICATION (VET)
MEDICATION

Use (kg) in Switzerland (2009): >250

Use (kg; approx.) in Germany (2009): ?7500

Use (kg; exact) in Germany (2009): 7475

Use (kg) in USA (2002): 463

Use (kg) in France (2004): 3346

Consumption (g per capita) in Switzerland (2009): 0.032

Consumption (g per capita; approx.) in Germany (2009): 0.092

Consumption (g per capita; exact) in Germany (2009): 0.091

Consumption (g per capita) in the USA (2002): 0.0016

Consumption (g per capita) in France (2004): 0.055

Excretion rate: 0.6

Calculated removal (%): 8.8

9.1.1 Use Classification

Animal Drugs -> FDA Approved Animal Drug Products (Green Book) -> Active Ingredients
Human Drugs -> FDA Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) -> Active Ingredients
Pharmaceuticals -> Animal Drugs -> Approved in Taiwan
S72 | NTUPHTW | Pharmaceutically Active Substances from National Taiwan University | DOI:10.5281/zenodo.3955664

9.2 Methods of Manufacturing

Prepn from guanidine and beta-ethoxy-3,4,5-trimethoxybenzylbenzalnitrile
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. 13th Edition, Whitehouse Station, NJ: Merck and Co., Inc., 2001., p. 1730
Trimethoprim /is a/ drug that /is/ made from vanillin.
Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed., Volumes 1-26. New York, NY: John Wiley and Sons, 1978-1984., p. V23 714 (1983)

9.3 Formulations / Preparations

Preparations: Tablets, 100 and 200 mg.
Hussar, D.A. (ed.). Modell's Drugs in Current Use and New Drugs. 38th ed. New York, NY: Springer Publishing Co., 1992., p. 165
Component of Bactrin and Septra
Kirk-Othmer Encyclopedia of Chemical Technology. 4th ed. Volumes 1: New York, NY. John Wiley and Sons, 1991-Present., p. V19 (1996) 784

9.4 General Manufacturing Information

See sulfamethoxazole, sulfadiazine, sulfametrole, sulfamoxole, and sulfalene for list of trade names of mixtures with trimethoprim.
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. 13th Edition, Whitehouse Station, NJ: Merck and Co., Inc., 2001., p. 1730
Authorized or allowed for use in aquaculture in certain European countries.
Kirk-Othmer Encyclopedia of Chemical Technology. 4th ed. Volumes 1: New York, NY. John Wiley and Sons, 1991-Present., p. V3 (1992) 618
Solid phase reactions between trimethoprim & sulfamethoxazole were investigated by IR spectrometry & differential scanning calorimetry in 4 tablet formulations. Heating & humidity were found to enhance the conditions for reactions, with the most likely manufacturing step causing reactions being wet granulation. Mixing, grinding & compression of powders caused no interactions.
Bettinetti GP, et al; Farmaco Ed. Prat. 38 (Jul): 159-164 (1983)

10 Identification

10.1 Analytic Laboratory Methods

Trimethoprim was determined in tablets and suspensions by HPLC using a Partisil 10 ODS-3 column, MeCN (25%)-NH4OAc (1%) in water as the mobile phase and detection at 254 nm. The detector response was linear between 1.0-500 ug/ml and the limit of detection was 0.2 ug/ml. The average recovery from tablets and suspensions was 99.4 and 99.1%, with standard deviation of 0.98 and 0.56%, respectively. The method is simple, accurate, and reproducible. Buffer components, sulfamethoxazole, and Me and Pr p-hydroxybenzoates caused no interference during the analysis. The method is suitable for the purity control of trimethoprim in dosage forms.
Bergh JJ et al; J Chromatogr 513: 392-6 (1990)
A HPLC method which uses a stainless-steel column packed with Zorbax TMS 7 mum and a mobile phase of MeCN-PrOH-MeOH-THF-AcOH-H2O (5:20:15:25:1:34) is suitable for determination of trimethoprim in pharmaceuticals in presence of degradation products. The method is stability-indicating as none of the degradation products interfered with the trimethoprim peak. There is also no interference from sulfamethoxazole, Me p-hydroxybenzoate and Pr p-hydroxybenzoate which are frequently present in trimethoprim formulations. The method is reproducible with recoveries of approx 100%.
Bergh JJ, Breytenbach JC; J Chromatogr 387: 528-31 (1987)

10.2 Clinical Laboratory Methods

Trimethoprim was determined in plasma and urine by HPLC on a column of Suplex pKb 100, a silica column whose silanol groups have been deactivated to prevent tailing of the peaks. Experiments were done to determine the optimum conditions of extraction from the biol fluids and of elution from the column. The method is suitable for pharmacokinetic studies. The limit of quantitation of each cmpd was 20 ng/ml plasma.
Alvinerie M et al; Analusis 19 (8): 244-8 (1991)
A simple and rapid method is developed for the analysis of trimethoprim in human plasma and urine by HPLC. It involves minimal sample preparation and single wavelength monitoring. The detection limit of the method is 0.1 ug/ml for trimethoprim, and covers the entire concn range normally encountered therapeutically.
Avgerinos A et al; J Pharm Biomed Anal 9 (6): 507-10 (1991)

11 Safety and Hazards

11.1 Hazards Identification

11.1.1 GHS Classification

1 of 2
View All
Note
Pictograms displayed are for 92.1% (129 of 140) of reports that indicate hazard statements. This chemical does not meet GHS hazard criteria for 7.9% (11 of 140) of reports.
Pictogram(s)
Irritant
Health Hazard
Environmental Hazard
Signal
Danger
GHS Hazard Statements

H302 (85%): Harmful if swallowed [Warning Acute toxicity, oral]

H361 (30.7%): Suspected of damaging fertility or the unborn child [Warning Reproductive toxicity]

H372 (26.4%): Causes damage to organs through prolonged or repeated exposure [Danger Specific target organ toxicity, repeated exposure]

H411 (26.4%): Toxic to aquatic life with long lasting effects [Hazardous to the aquatic environment, long-term hazard]

Precautionary Statement Codes

P203, P260, P264, P270, P273, P280, P301+P317, P318, P319, P330, P391, P405, and P501

(The corresponding statement to each P-code can be found at the GHS Classification page.)

ECHA C&L Notifications Summary

Aggregated GHS information provided per 140 reports by companies from 21 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

Reported as not meeting GHS hazard criteria per 11 of 140 reports by companies. For more detailed information, please visit ECHA C&L website.

There are 20 notifications provided by 129 of 140 reports by companies with hazard statement code(s).

Information may vary between notifications depending on impurities, additives, and other factors. The percentage value in parenthesis indicates the notified classification ratio from companies that provide hazard codes. Only hazard codes with percentage values above 10% are shown.

11.1.2 Hazard Classes and Categories

Acute Tox. 4 (85%)

Repr. 2 (30.7%)

STOT RE 1 (26.4%)

Aquatic Chronic 2 (26.4%)

Acute toxicity (Oral) - Category 3

Reproductive toxicity - Category 1A, Additional category: Effects on or via lactation

Specific target organ toxicity - Repeated exposure - Category 2 (skin, hematopoietic system)

Hazardous to the aquatic environment (Acute) - Category 2

Hazardous to the aquatic environment (Long-term) - Category 2

11.1.3 Health Hazards

SYMPTOMS: Symptoms of exposure to this compound may include rash, pruritis, dermatitis, epigastric distress, nausea, and vomiting.

ACUTE/CHRONIC HAZARDS: This material may cause skin irritation and rash. (NTP, 1992)

National Toxicology Program, Institute of Environmental Health Sciences, National Institutes of Health (NTP). 1992. National Toxicology Program Chemical Repository Database. Research Triangle Park, North Carolina.

11.1.4 Fire Hazards

Flash point data for this chemical are not available. It is probably combustible. (NTP, 1992)
National Toxicology Program, Institute of Environmental Health Sciences, National Institutes of Health (NTP). 1992. National Toxicology Program Chemical Repository Database. Research Triangle Park, North Carolina.

11.2 First Aid Measures

11.2.1 First Aid

EYES: First check the victim for contact lenses and remove if present. Flush victim's eyes with water or normal saline solution for 20 to 30 minutes while simultaneously calling a hospital or poison control center. Do not put any ointments, oils, or medication in the victim's eyes without specific instructions from a physician. IMMEDIATELY transport the victim after flushing eyes to a hospital even if no symptoms (such as redness or irritation) develop.

SKIN: IMMEDIATELY flood affected skin with water while removing and isolating all contaminated clothing. Gently wash all affected skin areas thoroughly with soap and water. If symptoms such as redness or irritation develop, IMMEDIATELY call a physician and be prepared to transport the victim to a hospital for treatment.

INHALATION: IMMEDIATELY leave the contaminated area; take deep breaths of fresh air. If symptoms (such as wheezing, coughing, shortness of breath, or burning in the mouth, throat, or chest) develop, call a physician and be prepared to transport the victim to a hospital. Provide proper respiratory protection to rescuers entering an unknown atmosphere. Whenever possible, Self-Contained Breathing Apparatus (SCBA) should be used; if not available, use a level of protection greater than or equal to that advised under Protective Clothing.

INGESTION: DO NOT INDUCE VOMITING. If the victim is conscious and not convulsing, give 1 or 2 glasses of water to dilute the chemical and IMMEDIATELY call a hospital or poison control center. Be prepared to transport the victim to a hospital if advised by a physician. If the victim is convulsing or unconscious, do not give anything by mouth, ensure that the victim's airway is open and lay the victim on his/her side with the head lower than the body. DO NOT INDUCE VOMITING. IMMEDIATELY transport the victim to a hospital. (NTP, 1992)

National Toxicology Program, Institute of Environmental Health Sciences, National Institutes of Health (NTP). 1992. National Toxicology Program Chemical Repository Database. Research Triangle Park, North Carolina.

11.3 Fire Fighting

Fires involving this material can be controlled with a dry chemical, carbon dioxide or Halon extinguisher. (NTP, 1992)
National Toxicology Program, Institute of Environmental Health Sciences, National Institutes of Health (NTP). 1992. National Toxicology Program Chemical Repository Database. Research Triangle Park, North Carolina.

11.4 Accidental Release Measures

11.4.1 Isolation and Evacuation

Excerpt from ERG Guide 154 [Substances - Toxic and/or Corrosive (Non-Combustible)]:

IMMEDIATE PRECAUTIONARY MEASURE: Isolate spill or leak area in all directions for at least 50 meters (150 feet) for liquids and at least 25 meters (75 feet) for solids.

SPILL: Increase the immediate precautionary measure distance, in the downwind direction, as necessary.

FIRE: If tank, rail tank car or highway tank is involved in a fire, ISOLATE for 800 meters (1/2 mile) in all directions; also, consider initial evacuation for 800 meters (1/2 mile) in all directions. (ERG, 2024)

11.4.2 Disposal Methods

SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices.

11.5 Handling and Storage

11.5.1 Nonfire Spill Response

SMALL SPILLS AND LEAKAGE: If a spill of this chemical occurs, FIRST REMOVE ALL SOURCES OF IGNITION, then you should dampen the solid spill material with acetone and transfer the dampened material to a suitable container. Use absorbent paper dampened with acetone to pick up any remaining material. Seal your contaminated clothing and the absorbent paper in a vapor-tight plastic bag for eventual disposal. Solvent wash all contaminated surfaces with acetone followed by washing with a soap and water solution. Do not reenter the contaminated area until the Safety Officer (or other responsible person) has verified that the area has been properly cleaned.

STORAGE PRECAUTIONS: You should store this chemical under refrigerated temperatures, and keep it away from oxidizing materials. (NTP, 1992)

National Toxicology Program, Institute of Environmental Health Sciences, National Institutes of Health (NTP). 1992. National Toxicology Program Chemical Repository Database. Research Triangle Park, North Carolina.

11.5.2 Storage Conditions

Trimethoprim tablets should be stored in tight, light-resistant containers at 15-30 °C in a dry place.
McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 92. Bethesda, MD: American Society of Hospital Pharmacists, Inc., 1992 (Plus Supplements 1992)., p. 453
Trimethoprim-sulfamethoxazole should be stored at room temp & not refrigerated. The multiple-dose vials should be used within 48 hr of initial entry. /Trimethoprim-sulfamethoxazole/
Trissel, L.A. Handbook on Injectable Drugs. 9th ed. Bethesda, MD. American Society of Health-System Pharmacists' Product Development. 1996., p. 1063

11.6 Exposure Control and Personal Protection

11.6.1 Personal Protective Equipment (PPE)

RECOMMENDED RESPIRATOR: Where the neat test chemical is weighed and diluted, wear a NIOSH-approved half face respirator equipped with an organic vapor/acid gas cartridge (specific for organic vapors, HCl, acid gas and SO2) with a dust/mist filter. (NTP, 1992)
National Toxicology Program, Institute of Environmental Health Sciences, National Institutes of Health (NTP). 1992. National Toxicology Program Chemical Repository Database. Research Triangle Park, North Carolina.

11.7 Stability and Reactivity

11.7.1 Air and Water Reactions

Insoluble in water.

11.7.2 Reactive Group

Amines, Phosphines, and Pyridines

Ethers

11.7.3 Reactivity Profile

This compound readily forms salts with acids. (NTP, 1992).
National Toxicology Program, Institute of Environmental Health Sciences, National Institutes of Health (NTP). 1992. National Toxicology Program Chemical Repository Database. Research Triangle Park, North Carolina.

11.8 Transport Information

11.8.1 DOT Label

Poison

11.9 Regulatory Information

The Australian Inventory of Industrial Chemicals
Chemical: 2,4-Pyrimidinediamine, 5-[(3,4,5-trimethoxyphenyl)methyl]-
New Zealand EPA Inventory of Chemical Status
Trimethoprim: Does not have an individual approval but may be used under an appropriate group standard

11.9.1 FDA Requirements

Manufacturers, packers, and distributors of drug and drug products for human use are responsible for complying with the labeling, certification, and usage requirements as prescribed by the Federal Food, Drug, and Cosmetic Act, as amended (secs 201-902, 52 Stat. 1040 et seq., as amended; 21 U.S.C. 321-392).
21 CFR 200-299, 300-499, 820, and 860 (4/1/2001)
Trimethoprim and sulfadiazine tablets. (a) Each tablet contains 30 mg (5 mg of trimethoprim and 25 mg of sulfadiazine), 120 mg (20 mg of trimethoprim and 100 mg of sulfadiazine), 480 mg (80 mg of trimethoprim and 400 mg of sulfadiazine) or 960 mg (160 mg of trimethoprim and 800 mg of sulfadiazine) ... (c) Conditions of use: (1) The drug is used in dogs where systemic antibacterial action against sensitive organisms is required, either alone or as an adjunct to surgery or debridement with associated infection. The drug is indicated where control of bacterial infection is required during the treatment of acute urinary tract infections, acute bacterial complications of distemper, acute respiratory tract infections, acute alimentary tract infections, wound infections, and abscesses. ... (6) The drug should not be used in patients showing marked liver parenchymal damage or blood dyscrasia, nor in those with a history of sulfonamide sensitivity. (7) Federal law restricts this drug to use by or on the order of a licensed veterinarian. /Trimethoprim and sulfadiazine/
21 CFR 520.2610 (4/1/2001)
Trimethoprim and sulfadiazine oral paste. (a) Each gram of oral paste contains 400 mg (67 mg of trimethoprim and 333 mg of sulfadiazine) ... (c) Conditions of use: ... (2) Indications for use: For horses where systemic anti-bacterial action against sensitive organisms is required during treatment of acute strangles, respiratory infections, acute urogenital infections, and wound infections and abscesses. /Trimethoprim and sulfadiazine/
21 CFR 520.2611 (4/1/2001)
Trimethoprim and sulfadiazine oral suspension. (a) Each ml of oral suspension contains 60 mg of drug (10 mg of trimethoprim and 50 mg of sulfadiazine) ... (c) Condition of use: Dogs: ... (2) Indications for use: The drug is used in dogs where systemic antibacterial action against sensitive organisms is required, either alone or as an adjunct to surgery or debridement with associated infection. The drug is indicated where control of bacterial infection is required during the treatment of acute urinary tract infections, acute bacterial complications of distemper, acute respiratory tract infections, acute alimentary tract infections, wound infections, and abscesses. ... Federal law restricts this drug to use by or on the order of a licensed veterinarian. /Trimethoprim and sulfadiazine/
21 CFR 520.2612 (4/1/2001)
For more FDA Requirements (Complete) data for TRIMETHOPRIM (7 total), please visit the HSDB record page.

12 Toxicity

12.1 Toxicological Information

12.1.1 USGS Health-Based Screening Levels for Evaluating Water-Quality

Chemical
Trimethoprim
Chemical Classes
Pharmaceutical
Reference
Smith, C.D. and Nowell, L.H., 2024. Health-Based Screening Levels for evaluating water-quality data (3rd ed.). DOI:10.5066/F71C1TWP

12.1.2 Drug Induced Liver Injury

Compound
trimethoprim
DILI Annotation
Less-DILI-Concern
Severity Grade
4
Label Section
Adverse reactions
References

M Chen, V Vijay, Q Shi, Z Liu, H Fang, W Tong. FDA-Approved Drug Labeling for the Study of Drug-Induced Liver Injury, Drug Discovery Today, 16(15-16):697-703, 2011. PMID:21624500 DOI:10.1016/j.drudis.2011.05.007

M Chen, A Suzuki, S Thakkar, K Yu, C Hu, W Tong. DILIrank: the largest reference drug list ranked by the risk for developing drug-induced liver injury in humans. Drug Discov Today 2016, 21(4): 648-653. PMID:26948801 DOI:10.1016/j.drudis.2016.02.015

12.1.3 Effects During Pregnancy and Lactation

◉ Summary of Use during Lactation

Because of the low levels of trimethoprim in breastmilk, amounts ingested by the infant are small and would not be expected to cause any adverse effects in breastfed infants.

◉ Effects in Breastfed Infants

In one study, no adverse effects were noted in infants during 4 days of maternal therapy with co-trimoxazole.

In a telephone follow-up study, 12 nursing mothers reported taking co-trimoxazole (dosage unspecified). Two mothers reported poor feeding in their infants. Diarrhea was not reported among the exposed infants.

◉ Effects on Lactation and Breastmilk

Relevant published information was not found as of the revision date.

12.1.4 Acute Effects

12.1.5 Interactions

Concomitant admin of trimethoprim or trimethoprim/sulfamethoxazole with methotrexate may incr bone marrow suppression, probably as an additive antifolate effect.
American Medical Association. AMA Drug Evaluations Annual 1991. Chicago, IL: American Medical Association, 1991., p. 1723
Concurrent use with trimethoprim or use of trimethoprim between courses of other folic acid antagonists, such as methotrexate or pyrimethamine, is not recommended because of the possibility of an increased incidence of megaloblastic anemia.
MICROMEDEX Thomson Health Care. USPDI - Drug Information for the Health Care Professional. 22nd ed. Volume 1. MICROMEDEX Thomson Health Care, Greenwood Village, CO. 2002. Content Reviewed and Approved by the U.S. Pharmacopeial Convention, Inc., p. 2850
Trimethoprim may inhibit the metab of phenytoin, increasing the half-life of phenytoin by up to 50% & decreasing its clearance by 30%.
MICROMEDEX Thomson Health Care. USPDI - Drug Information for the Health Care Professional. 22nd ed. Volume 1. MICROMEDEX Thomson Health Care, Greenwood Village, CO. 2002. Content Reviewed and Approved by the U.S. Pharmacopeial Convention, Inc., p. 2850
Concurrent use /with rifampin/ may significantly increase the elimination and shorten the elimination half-life of trimethoprim.
MICROMEDEX Thomson Health Care. USPDI - Drug Information for the Health Care Professional. 22nd ed. Volume 1. MICROMEDEX Thomson Health Care, Greenwood Village, CO. 2002. Content Reviewed and Approved by the U.S. Pharmacopeial Convention, Inc., p. 2850
For more Interactions (Complete) data for TRIMETHOPRIM (15 total), please visit the HSDB record page.

12.1.6 Antidote and Emergency Treatment

For most patients with trimethoprim or TMP-SMX overdose, symptomatic & supportive treatment is indicated. Patients require hematologic monitoring. Gastric emptying, if performed within a few hr of ingestion, may aid in removing some of the drug & prevent rapid induction of toxic serum levels. Activated charcoal has been used, but its efficacy, as well as that of cathartics, has not been studied. Acidification of the urine may enhance the elimination of trimethoprim but is generally not recommended. Hemodialysis may remove only moderate amounts of trimethoprim in view of its protein binding & large volume of distribution.
Ellenhorn, M.J., S. Schonwald, G. Ordog, J. Wasserberger. Ellenhorn's Medical Toxicology: Diagnosis and Treatment of Human Poisoning. 2nd ed. Baltimore, MD: Williams and Wilkins, 1997., p. 236
Patients should be hospitalized where cardiac monitoring, iv fluids, & oxygen, if required, are available. Hematologic evaluation should be performed including a bone marrow study according to clinical judgment. Seizures can be treated with diazepam. Electrolytes should be determined & replaced together with adequate fluid replacement. Patients should be followed for any evidence of hematologic depression both in hospital & as outpatients in the following wks. If patients are asymptomatic & able to eat without difficulty, they can be discharged to be followed as outpatients.
Ellenhorn, M.J., S. Schonwald, G. Ordog, J. Wasserberger. Ellenhorn's Medical Toxicology: Diagnosis and Treatment of Human Poisoning. 2nd ed. Baltimore, MD: Williams and Wilkins, 1997., p. 236
/SRP:/ Basic treatment: Establish a patent airway. Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with normal saline during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 ml/kg up to 200 ml of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poison A and B/
Bronstein, A.C., P.L. Currance; Emergency Care for Hazardous Materials Exposure. 2nd ed. St. Louis, MO. Mosby Lifeline. 1994., p. 139
/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in respiratory arrest. Positive pressure ventilation techniques with a bag valve mask device may be beneficial. Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start an IV with D5W /SRP: "To keep open", minimal flow rate/. Use lactated Ringer's if signs of hypovolemia are present. Watch for signs of fluid overload. Consider drug therapy for pulmonary edema ... . For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam (Valium) ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poison A and B/
Bronstein, A.C., P.L. Currance; Emergency Care for Hazardous Materials Exposure. 2nd ed. St. Louis, MO. Mosby Lifeline. 1994., p. 139

12.1.7 Human Toxicity Excerpts

In a surveillance study of Michigan Medicaid recipients involving 229,101 completed pregnancies conducted between 1985 & 1992, 2296 newborns had been exposed to the combination of trimethoprim-sulfamethoxazole during the 1st trimester. A total of 126 (5.5%) major birth defects were observed (98 expected). This incidence is suggestive of an association between the drug combination & congenital defects. Specific data were available for six defect categories, including (observed/expected) 37/23 cardiovascular defects ... .
Briggs, G.G, R.K. Freeman, S.J. Yaffe. A Reference Guide to Fetal and Neonatal Risk. Drugs in Pregnancy and Lactation. 4th ed. Baltimore, MD: Williams & Wilkins 1994., p. 847
Sulfonamide/trimethoprim combinations have been shown to cause a drop in the sperm count after 1 month of continuous treatment in males. Decreases varied between 7 & 88%. the authors theorized that trimethoprim deprived the spermatogenetic cells of active folate by inhibiting dihydrofolate reductase.
Briggs, G.G, R.K. Freeman, S.J. Yaffe. A Reference Guide to Fetal and Neonatal Risk. Drugs in Pregnancy and Lactation. 4th ed. Baltimore, MD: Williams & Wilkins 1994., p. 848
Single case report of Niikawa-Kuroki syndrome (mental & physical growth retardation & craniofacial anomalies) in non-Japanese girl.
Young, L.Y., M.A. Koda-Kimble (eds.). Applied Therapeutics. The Clinical Use of Drugs. 6th ed. Vancouver, WA., Applied Therapeutics, Inc. 1995., p. 45-20
Trimethoprim poisoning has been characterized by nausea, vomiting, headache, swollen face, epigastric pain, & weakness.
Ellenhorn, M.J., S. Schonwald, G. Ordog, J. Wasserberger. Ellenhorn's Medical Toxicology: Diagnosis and Treatment of Human Poisoning. 2nd ed. Baltimore, MD: Williams and Wilkins, 1997., p. 236
For more Human Toxicity Excerpts (Complete) data for TRIMETHOPRIM (11 total), please visit the HSDB record page.

12.1.8 Non-Human Toxicity Excerpts

Trimethoprim has not been shown to cause adverse effects on fertility or reproductive performance in rats given oral doses as high as 70 mg/kg of body weight daily in males and 14 mg/kg of body weight daily in females.
MICROMEDEX Thomson Health Care. USPDI - Drug Information for the Health Care Professional. 22nd ed. Volume 1. MICROMEDEX Thomson Health Care, Greenwood Village, CO. 2002. Content Reviewed and Approved by the U.S. Pharmacopeial Convention, Inc., p. 2849
Studies in rats given oral doses of 70 mg/kg daily during the third trimester and throughout parturition have not shown that trimethoprim causes adverse effects on gestation or pup growth and survival. However, studies in rats given doses of 40 times the human dose have shown that trimethoprim is teratogenic. Studies in rabbits given doses of 6 times the human dose have shown an increase in fetal loss (dead, resorbed, and malformed fetuses).
MICROMEDEX Thomson Health Care. USPDI - Drug Information for the Health Care Professional. 22nd ed. Volume 1. MICROMEDEX Thomson Health Care, Greenwood Village, CO. 2002. Content Reviewed and Approved by the U.S. Pharmacopeial Convention, Inc., p. 2849
A combination of sulphadiazine & trimethoprim at a ratio of 5:1 (SDZ/TMP) was tested for possible immunomodulatory effects. The aim of the study was to follow the immune response after vaccination with simultaneous drug treatment. The fish were immunised with a commercial oil-based divalent (furunculosis/ vibriosis) vaccine & were simultaneously given oral drug treatment. The specific immune response was monitored by analysing the levels of specific antibodies with ELISA. As indicators of the nonspecific immune response, the lysozyme activity of serum was measured & the phagocytic activity of circulating leucocytes was monitored by a chemiluminescence assay. Total circulating leucocyte counts & differentials were also monitored. The disease resistance was evaluated by challenge tests at the end of the experiment. The results indicate that SDZ/TMP at a ratio of 5:1 does not interfere negatively with the immune response in rainbow trout after vaccination. A slight stimulation in the antibody response as well as in the chemiluminescence response of circulating granulocytes was recorded in fish treated with the drugs in connection with vaccination. The drugs did not significantly affect the survival after challenge.
Lunden T, Bylund G; Vet Immunol Immunopathol 85 (1-2): 99-108 (2002)

12.1.9 Non-Human Toxicity Values

LD50 Mice oral 7000 mg/kg
Budavari, S. (ed.). The Merck Index - Encyclopedia of Chemicals, Drugs and Biologicals. Rahway, NJ: Merck and Co., Inc., 1989., p. 1528
LD50 Rat oral 200 mg/kg
Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996., p. 3280
LD50 Mouse oral 3960 mg/kg
Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996., p. 3280
LD50 Mouse ip 1870 mg/kg
Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996., p. 3280
LD50 Mouse iv 200 mg/kg
Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996., p. 3280

12.1.10 Protein Binding

Trimethoprim is 44% bound to plasma proteins, though the specific proteins to which it binds have not been elucidated.

12.2 Ecological Information

12.2.1 Environmental Fate / Exposure Summary

Trimethoprim's production and use as an antibiotic may result in its release to the environment through various waste streams. If released to air, an estimated vapor pressure of 9.9X10-9 mm Hg at 25 °C indicates trimethoprim will exist solely in the particulate phase in the ambient atmosphere. Particulate-phase trimethoprim will be removed from the atmosphere by wet and dry deposition. If released to soil, trimethoprim is expected to have high mobility based upon an estimated Koc of 75. Trimethoprim has a pKa of 7.12, which indicates it will partially exist in the protonated form in moist soils and cations adsorb to soil stronger than neutral compounds. Volatilization from moist soil surfaces is not expected to be an important fate process based upon an estimated Henry's Law constant of 2.4X10-14 atm-cu m/mole for the free base and given the fact that cations are non-volatile. Trimethoprim is not expected to volatilize from dry soil surfaces based on its estimated vapor pressure. The half-lives of trimethoprim incorporated into sediment cores were approximately 100 and 75 days under anaerobic and aerobic conditions, respectively, suggesting that biodegradation occurs slowly in the environment. If released into water, the neutral form of trimethoprim is not expected to adsorb to suspended solids and sediment based upon the estimated Koc. Since cations tend to adsorb to suspended solids and sediment in water, the protonated form of trimethoprim is expected to adsorb to these surfaces. Volatilization from water surfaces is not expected to be an important fate process based upon this compound's estimated Henry's Law constant and the fact that cations are non-volatile. Hydrolysis is not expected to be an important fate process due to a lack of hydrolyzable functional groups. An estimated BCF of 3 suggests the potential for bioconcentration in aquatic organisms is low. Occupational exposure to trimethoprim may occur through inhalation of dust particles and dermal contact with this compound at workplaces where trimethoprim is produced or used. The general population may be exposed to trimethoprim through its use as an antibiotic. (SRC)

12.2.2 Artificial Pollution Sources

Trimethoprim's production and use as an antibiotic(1,2) may result in its release to the environment through various waste streams(SRC).
(1) Budvari S; Merck Index. 13th ed, Whitehouse Station, NJ Merck & Co. p 1720 (2001)
(2) Nipales NS et al; pp. 104-6 in Amer Chem Soc Div Environ Chem. Preprint abstract 219th ACS Nat Meeting (2000)

12.2.3 Environmental Fate

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 75(SRC), determined from a measured log Kow of 0.91(2) and a regression-derived equation(3), indicates that trimethoprim is expected to have high mobility in soil(SRC). Trimethoprim has a pKa of 7.12(4), which indicates it will partially exist in the protonated form in moist soils and cations adsorb to soil stronger than neutral compounds(SRC). Volatilization of trimethoprim from moist soil surfaces is not expected to be an important fate process(SRC) because cations are non-volatile and the neutral species has an estimated Henry's Law constant of 2.4X10-14 atm-cu m/mole(SRC), developed using a fragment constant estimation method(4). Trimethoprim is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 9.9X10-9 mm Hg(SRC), determined from a fragment constant method(6). Trimethoprim is expected to biodegrade slowly in soils based upon biodegradation half-lives of approximately 100 and 75 days under anaerobic and aerobic conditions, respectively, in sediment(7).
(1) Swann RL et al; Res Rev 85: 17-28 (1983)
(2) Hansch C et al; Exploring QSAR. Hydrophobic, Electronic, and Steric Constants. ACS Prof Ref Book. Heller SR, consult. ed., Washington, DC: Amer Chem Soc p. 124 (1995)
(3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 4-9 (1990)
(4) Perrin DD; Dissociation Constants of Organic Bases in Aqueous Solution. London, UK: Butterworth (1965)
(5) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991)
(6) Lyman WJ; p. 31 in Environmental Exposure From Chemicals Vol I, Neely WB, Blau GE, eds, Boca Raton, FL: CRC Press (1985)
(7) Hektoen H et al; Aquaculture 133: 175-84 (1995)
AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 75(SRC), determined from a measured log Kow of 0.91(2) and a regression-derived equation(3), indicates that trimethoprim is not expected to adsorb to suspended solids and sediment(SRC). Trimethoprim has a pKa of 7.12(4), which indicates it will partially exist in the protonated form in water surfaces and the cation may adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is not expected(3) based upon an estimated Henry's Law constant of 2.4X10-14 atm-cu m/mole(SRC), developed using a fragment constant estimation method(5), and the fact that cations do not volatilize. According to a classification scheme(6), an estimated BCF of 3(SRC), from its log Kow(2) and a regression-derived equation(7), suggests the potential for bioconcentration in aquatic organisms is low(SRC). Although trimethoprim absorbs light greater than 290 nm, it was shown to be stable in seawater exposed to sunlight(8). The half-lives of trimethoprim incorporated into sediment cores were approximately 100 and 75 days under anaerobic and aerobic conditions, respectively(9).
(1) Swann RL et al; Res Rev 85: 17-28 (1983)
(2) Hansch C et al; Exploring QSAR. Hydrophobic, Electronic, and Steric Constants. ACS Prof Ref Book. Heller SR, consult. ed., Washington, DC: Amer Chem Soc p. 124 (1995)
(3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 4-9, 15-1 to 15-29 (1990)
(4) Perrin DD; Dissociation Constants of Organic Bases in Aqueous Solution. London, UK: Butterworth (1965)
(5) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991)
(6) Franke C et al; Chemosphere 29: 1501-14 (1994)
(7) Meylan WM et al; Environ Toxicol Chem 18: 664-72 (1999)
(8) Fjelde S; pp. 285-88 in Residues Vet Drugs Food Proc Euroside Conf. Haagmsa N et al, eds. Utrecht, Netherlands (1993)
(9) Hektoen H et al; Aquaculture 133: 175-84 (1995)
ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), trimethoprim, which has a an estimated vapor pressure of 9.9X10-9 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), is expected to exist solely in the particulate phase in the ambient atmosphere. Particulate-phase trimethoprim may be removed from the air by wet and dry deposition(SRC).
(1) Bidleman TF; Environ Sci Technol 22: 361-367 (1988)
(2) Lyman WJ; p. 31 in Environmental Exposure From Chemicals Vol I, Neely WB, Blau GE, eds, Boca Raton, FL: CRC Press (1985)
(3) Meylan WM, Howard PH; Chemosphere 26: 2293-99 (1993)

12.2.4 Environmental Biodegradation

Trimethoprim incorporated in sediment cores in a Norwegian fjord was found to be moderately persistent, with a half-life of approximately 100 days when buried at a depth of 6-7 cm(1). The half-life in surface sediment was about 75 days(1).
(1) Hektoen H et al; Aquaculture 133: 175-84(1995)

12.2.5 Environmental Abiotic Degradation

The pKa of trimethoprim is 7.12(1), which indicates that this compound will partially exist in the protonated form in the environment(SRC). Trimethoprim absorbs light greater than 290 nm(2). However it was found to be stable in seawater for up to 20 weeks when exposed to UV light(2).
(1) Perrin DD; Dissociation Constants of Organic Bases in Aqueous Solution. London, UK: Butterworth (1965)
(2) Fjelde S; pp. 285-88 in Residues Vet Drugs Food Proc Euroside Conf. Haagmsa N et al, eds. Utrecht, Netherlands (1993)

12.2.6 Environmental Bioconcentration

An estimated BCF of 3 was calculated for trimethoprim(SRC), using a log Kow of 0.91(1) and a regression-derived equation(2). According to a classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic organisms is low (SRC).
(1) Hansch C et al; Exploring QSAR. Hydrophobic, Electronic, and Steric Constants. ACS Prof Ref Book. Heller SR, consult. ed., Washington, DC: Amer Chem Soc p. 124 (1995)
(2) Meylan WM et al; Environ Toxicol Chem 18: 664-72 (1999)
(3) Franke C et al; Chemosphere 29: 1501-14 (1994)

12.2.7 Soil Adsorption / Mobility

The Koc of trimethoprim is estimated as 75(SRC), using a measured log Kow of 0.91(1) and a regression-derived equation(2). According to a classification scheme(3), this estimated Koc value suggests that trimethoprim is expected to have high mobility in soil(SRC). The pKa of trimethoprim is 7.12(4), which indicates that this compound will partially exist in the protonated form and cations adsorb to soil stronger than neutral compounds(SRC).
(1) Hansch C et al; Exploring QSAR. Hydrophobic, Electronic, and Steric Constants. ACS Prof Ref Book. Heller SR, consult. ed., Washington, DC: Amer Chem Soc p. 124 (1995)
(2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 4-9 (1990)
(3) Swann RL et al; Res Rev 85: 17-28 (1983)
(4) Perrin DD; Dissociation Constants of Organic Bases in Aqueous Solution. London, UK: Butterworth (1965)

12.2.8 Volatilization from Water / Soil

The Henry's Law constant for trimethoprim is estimated as 2.4X10-14 atm-cu m/mole(SRC) using a fragment constant estimation method(1). This Henry's Law constant indicates that trimethoprim is expected to be essentially nonvolatile from water surfaces(2). Furthermore, the pKa of trimethoprim is 7.12(3), which indicates that this compound will partially exist in the protonated form in the environment, and cation are non-volatile(SRC). Trimethoprim's Henry's Law constant(1) indicates that volatilization from moist soil surfaces is not expected(SRC). Trimethoprim is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 9.9X10-9 mm Hg(SRC), determined from a fragment constant method(4).
(1) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991)
(2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 15-1 to 15-29 (1990)
(3) Perrin DD; Dissociation Constants of Organic Bases in Aqueous Solution. London, UK: Butterworth (1965)
(4) Lyman WJ; p. 31 in Environmental Exposure From Chemicals Vol I, Neely WB, Blau GE, eds, Boca Raton, FL: CRC Press (1985)

12.2.9 Environmental Water Concentrations

SURFACE WATER: Trimethoprim was detected in 10 out of 52 surface water samples in Germany at a max concn of 0.20 ug/l(1). In a survey conducted by the United States geological Survey, trimethroprin, analyzed by two differing methods, was detected at maximum concentrations of 0.71 and 0.30 ug/l (0.0.15 and 0.013 ug/l median concns, 0.03 and 0.014 ug/l reporting levels) at a 12.5 and 27.4% frequency in 104 and 84 submitted water samples from a network of 139 US stream sampling sites across 30 states during 1999-2000(2). GROUNDWATER: Trimethoprim was not detected in any of the 59 groundwater samples analyzed in Germany(1).
(1) Hirsch R et al; Sci Total Environ 225: 109-118 (1999)
(2) Kolpin DW et al; Environ Sci Technol 36: 1202-11 (2002)

12.2.10 Effluent Concentrations

Trimethoprim was detected in 9 out of 10 sewage treatment plant effluents in Germany at a max concn of 0.66 ug/l and a median value of 0.32 ug/l(1).
(1) Hirsch R et al; Sci Total Environ 225: 109-118 (1999)

12.2.11 Milk Concentrations

Trimethoprim is distributed into milk in concentrations approximately 125% those of concurrent maternal serum concentrations.
McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 92. Bethesda, MD: American Society of Hospital Pharmacists, Inc., 1992 (Plus Supplements 1992)., p. 454
Trimethoprim is excreted into breast milk in low concns.
Briggs, G.G, R.K. Freeman, S.J. Yaffe. A Reference Guide to Fetal and Neonatal Risk. Drugs in Pregnancy and Lactation. 4th ed. Baltimore, MD: Williams & Wilkins 1994., p. 848

12.2.12 Probable Routes of Human Exposure

Occupational exposure to trimethoprim may occur through inhalation and dermal contact with this compound at workplaces where trimethoprim is produced or used. The general population may be exposed to trimethoprim through its use as an antibiotic. (SRC)

12.2.13 Average Daily Intake

The annual amount of trimethoprim prescribed to humans in Sweden in 1998 was 812 kg(1). This amounted to an annual total of 0.115 grams/person for the entire Swedish population(1).
(1) Nipales NS et al; pp. 104-6 in Amer Chem Soc Div Environ Chem. Preprint abstract 219th ACS Nat Meeting (2000)

12.2.14 Body Burden

Trimethoprim is distributed into milk in concentrations approximately 125% those of concurrent maternal serum concentrations.
McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 92. Bethesda, MD: American Society of Hospital Pharmacists, Inc., 1992 (Plus Supplements 1992)., p. 454

13 Associated Disorders and Diseases

14 Literature

14.1 Consolidated References

14.2 NLM Curated PubMed Citations

14.3 Springer Nature References

14.4 Thieme References

14.5 Wiley References

14.6 Nature Journal References

14.7 Chemical Co-Occurrences in Literature

14.8 Chemical-Gene Co-Occurrences in Literature

14.9 Chemical-Disease Co-Occurrences in Literature

15 Patents

15.1 Depositor-Supplied Patent Identifiers

15.2 WIPO PATENTSCOPE

15.3 FDA Green Book Patents

15.4 Chemical Co-Occurrences in Patents

15.5 Chemical-Disease Co-Occurrences in Patents

15.6 Chemical-Gene Co-Occurrences in Patents

16 Interactions and Pathways

16.1 Protein Bound 3D Structures

16.1.1 Ligands from Protein Bound 3D Structures

PDBe Ligand Code
PDBe Structure Code
PDBe Conformer

16.2 Chemical-Target Interactions

16.3 Drug-Drug Interactions

16.4 Pathways

17 Biological Test Results

17.1 BioAssay Results

18 Classification

18.1 MeSH Tree

18.2 NCI Thesaurus Tree

18.3 ChEBI Ontology

18.4 KEGG: USP

18.5 KEGG: ATC

18.6 KEGG: Animal Drugs

18.7 KEGG: Drug Groups

18.8 KEGG : Antimicrobials

18.9 WHO ATC Classification System

18.10 FDA Pharm Classes

18.11 ChemIDplus

18.12 CAMEO Chemicals

18.13 ChEMBL Target Tree

18.14 UN GHS Classification

18.15 EPA CPDat Classification

18.16 NORMAN Suspect List Exchange Classification

18.17 CCSBase Classification

18.18 EPA DSSTox Classification

18.19 FDA Drug Type and Pharmacologic Classification

18.20 EPA Substance Registry Services Tree

18.21 MolGenie Organic Chemistry Ontology

19 Information Sources

  1. Australian Industrial Chemicals Introduction Scheme (AICIS)
    2,4-Pyrimidinediamine, 5-[(3,4,5-trimethoxyphenyl)methyl]-
    https://services.industrialchemicals.gov.au/search-inventory/
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    https://cameochemicals.noaa.gov/help/reference/terms_and_conditions.htm?d_f=false
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    https://cameochemicals.noaa.gov/browse/react
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    https://creativecommons.org/licenses/by-nc/4.0/
  4. ChemIDplus
    ChemIDplus Chemical Information Classification
    https://pubchem.ncbi.nlm.nih.gov/source/ChemIDplus
  5. DrugBank
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    Creative Common's Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/legalcode)
    https://www.drugbank.ca/legal/terms_of_use
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    https://www.cancer.gov/policies/copyright-reuse
  7. EPA DSSTox
    CompTox Chemicals Dashboard Chemical Lists
    https://comptox.epa.gov/dashboard/chemical-lists/
  8. European Chemicals Agency (ECHA)
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    Use of the information, documents and data from the ECHA website is subject to the terms and conditions of this Legal Notice, and subject to other binding limitations provided for under applicable law, the information, documents and data made available on the ECHA website may be reproduced, distributed and/or used, totally or in part, for non-commercial purposes provided that ECHA is acknowledged as the source: "Source: European Chemicals Agency, http://echa.europa.eu/". Such acknowledgement must be included in each copy of the material. ECHA permits and encourages organisations and individuals to create links to the ECHA website under the following cumulative conditions: Links can only be made to webpages that provide a link to the Legal Notice page.
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    https://www.fda.gov/about-fda/about-website/website-policies#linking
  10. Hazardous Substances Data Bank (HSDB)
  11. Human Metabolome Database (HMDB)
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    http://www.hmdb.ca/citing
  12. New Zealand Environmental Protection Authority (EPA)
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  13. BindingDB
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  14. Comparative Toxicogenomics Database (CTD)
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    It is to be used only for research and educational purposes. Any reproduction or use for commercial purpose is prohibited without the prior express written permission of NC State University.
    http://ctdbase.org/about/legal.jsp
  15. Therapeutic Target Database (TTD)
  16. ChEBI
  17. FDA Pharm Classes
    LICENSE
    Unless otherwise noted, the contents of the FDA website (www.fda.gov), both text and graphics, are not copyrighted. They are in the public domain and may be republished, reprinted and otherwise used freely by anyone without the need to obtain permission from FDA. Credit to the U.S. Food and Drug Administration as the source is appreciated but not required.
    https://www.fda.gov/about-fda/about-website/website-policies#linking
  18. NCI Thesaurus (NCIt)
    LICENSE
    Unless otherwise indicated, all text within NCI products is free of copyright and may be reused without our permission. Credit the National Cancer Institute as the source.
    https://www.cancer.gov/policies/copyright-reuse
  19. Open Targets
    LICENSE
    Datasets generated by the Open Targets Platform are freely available for download.
    https://platform-docs.opentargets.org/licence
  20. CCSbase
    CCSbase Classification
    https://ccsbase.net/
  21. NORMAN Suspect List Exchange
    LICENSE
    Data: CC-BY 4.0; Code (hosted by ECI, LCSB): Artistic-2.0
    https://creativecommons.org/licenses/by/4.0/
    TRIMETHOPRIM
    NORMAN Suspect List Exchange Classification
    https://www.norman-network.com/nds/SLE/
  22. ChEMBL
    LICENSE
    Access to the web interface of ChEMBL is made under the EBI's Terms of Use (http://www.ebi.ac.uk/Information/termsofuse.html). The ChEMBL data is made available on a Creative Commons Attribution-Share Alike 3.0 Unported License (http://creativecommons.org/licenses/by-sa/3.0/).
    http://www.ebi.ac.uk/Information/termsofuse.html
  23. ClinicalTrials.gov
    LICENSE
    The ClinicalTrials.gov data carry an international copyright outside the United States and its Territories or Possessions. Some ClinicalTrials.gov data may be subject to the copyright of third parties; you should consult these entities for any additional terms of use.
    https://clinicaltrials.gov/ct2/about-site/terms-conditions#Use
  24. Crystallography Open Database (COD)
    LICENSE
    All data in the COD and the database itself are dedicated to the public domain and licensed under the CC0 License. Users of the data should acknowledge the original authors of the structural data.
    https://creativecommons.org/publicdomain/zero/1.0/
  25. The Cambridge Structural Database
  26. DailyMed
  27. Drug Induced Liver Injury Rank (DILIrank) Dataset
    LICENSE
    Unless otherwise noted, the contents of the FDA website (www.fda.gov), both text and graphics, are not copyrighted. They are in the public domain and may be republished, reprinted and otherwise used freely by anyone without the need to obtain permission from FDA. Credit to the U.S. Food and Drug Administration as the source is appreciated but not required.
    https://www.fda.gov/about-fda/about-website/website-policies#linking
  28. IUPAC Digitized pKa Dataset
    pyrimidine, 2,4-diamino-5-(3',4',5'-trimethoxybenzyl)-
    https://github.com/IUPAC/Dissociation-Constants
  29. Drugs and Lactation Database (LactMed)
  30. Drugs@FDA
    LICENSE
    Unless otherwise noted, the contents of the FDA website (www.fda.gov), both text and graphics, are not copyrighted. They are in the public domain and may be republished, reprinted and otherwise used freely by anyone without the need to obtain permission from FDA. Credit to the U.S. Food and Drug Administration as the source is appreciated but not required.
    https://www.fda.gov/about-fda/about-website/website-policies#linking
  31. WHO Model Lists of Essential Medicines
    LICENSE
    Permission from WHO is not required for the use of WHO materials issued under the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Intergovernmental Organization (CC BY-NC-SA 3.0 IGO) license.
    https://www.who.int/about/policies/publishing/copyright
  32. EPA Chemical and Products Database (CPDat)
  33. EU Clinical Trials Register
  34. NITE-CMC
    2,4-Diamino-5-(3,4,5-trimethoxybenzyl)pyrimidine [Trimethoprim] - FY2017 (New/original classication)
    https://www.chem-info.nite.go.jp/chem/english/ghs/17-mhlw-0016e.html
  35. FDA Approved Animal Drug Products (Green Book)
    LICENSE
    Unless otherwise noted, the contents of the FDA website (www.fda.gov), both text and graphics, are not copyrighted. They are in the public domain and may be republished, reprinted and otherwise used freely by anyone without the need to obtain permission from FDA. Credit to the U.S. Food and Drug Administration as the source is appreciated but not required.
    https://www.fda.gov/about-fda/about-website/website-policies#linking
  36. FDA Orange Book
    LICENSE
    Unless otherwise noted, the contents of the FDA website (www.fda.gov), both text and graphics, are not copyrighted. They are in the public domain and may be republished, reprinted and otherwise used freely by anyone without the need to obtain permission from FDA. Credit to the U.S. Food and Drug Administration as the source is appreciated but not required.
    https://www.fda.gov/about-fda/about-website/website-policies#linking
  37. National Drug Code (NDC) Directory
    LICENSE
    Unless otherwise noted, the contents of the FDA website (www.fda.gov), both text and graphics, are not copyrighted. They are in the public domain and may be republished, reprinted and otherwise used freely by anyone without the need to obtain permission from FDA. Credit to the U.S. Food and Drug Administration as the source is appreciated but not required.
    https://www.fda.gov/about-fda/about-website/website-policies#linking
  38. MassBank of North America (MoNA)
    LICENSE
    The content of the MoNA database is licensed under CC BY 4.0.
    https://mona.fiehnlab.ucdavis.edu/documentation/license
  39. NIST Mass Spectrometry Data Center
    LICENSE
    Data covered by the Standard Reference Data Act of 1968 as amended.
    https://www.nist.gov/srd/public-law
  40. SpectraBase
    2,4-DIAMINO-5-(3,4,5-TRIMETHOXYBENZYL)-PYRIMIDINE
    https://spectrabase.com/spectrum/lfor97OAy1
    2,4-DIAMINO-5-(3,4,5-TRIMETHOXYBENZYL)-PYRIMIDINE
    https://spectrabase.com/spectrum/Gx8XgBLlmw9
    2,4-DIAMINO-5-(3,4,5-TRIMETHOXYBENZYL)PYRIMIDINE
    https://spectrabase.com/spectrum/Dyhc4SPHbbk
    2,4-diamino-5-(3,4,5-trimethoxybenzyl)pyrimidine
    https://spectrabase.com/spectrum/4pdY6uYrm2c
    2,4-diamino-5-(3,4,5-trimethoxybenzyl)pyrimidine
    https://spectrabase.com/spectrum/EHyY9BkzGOq
  41. Japan Chemical Substance Dictionary (Nikkaji)
  42. KEGG
    LICENSE
    Academic users may freely use the KEGG website. Non-academic use of KEGG generally requires a commercial license
    https://www.kegg.jp/kegg/legal.html
    Anatomical Therapeutic Chemical (ATC) classification
    http://www.genome.jp/kegg-bin/get_htext?br08303.keg
  43. MassBank Europe
  44. Metabolomics Workbench
  45. Nature Chemical Biology
  46. NIPH Clinical Trials Search of Japan
  47. NLM RxNorm Terminology
    LICENSE
    The RxNorm Terminology is created by the National Library of Medicine (NLM) and is in the public domain and may be republished, reprinted and otherwise used freely by anyone without the need to obtain permission from NLM. Credit to the U.S. National Library of Medicine as the source is appreciated but not required. The full RxNorm dataset requires a free license.
    https://www.nlm.nih.gov/research/umls/rxnorm/docs/termsofservice.html
  48. WHO Anatomical Therapeutic Chemical (ATC) Classification
    LICENSE
    Use of all or parts of the material requires reference to the WHO Collaborating Centre for Drug Statistics Methodology. Copying and distribution for commercial purposes is not allowed. Changing or manipulating the material is not allowed.
    https://www.whocc.no/copyright_disclaimer/
  49. PharmGKB
    LICENSE
    PharmGKB data are subject to the Creative Commons Attribution-ShareALike 4.0 license (https://creativecommons.org/licenses/by-sa/4.0/).
    https://www.pharmgkb.org/page/policies
  50. Pharos
    LICENSE
    Data accessed from Pharos and TCRD is publicly available from the primary sources listed above. Please respect their individual licenses regarding proper use and redistribution.
    https://pharos.nih.gov/about
  51. Protein Data Bank in Europe (PDBe)
  52. RCSB Protein Data Bank (RCSB PDB)
    LICENSE
    Data files contained in the PDB archive (ftp://ftp.wwpdb.org) are free of all copyright restrictions and made fully and freely available for both non-commercial and commercial use. Users of the data should attribute the original authors of that structural data.
    https://www.rcsb.org/pages/policies
  53. Springer Nature
  54. Thieme Chemistry
    LICENSE
    The Thieme Chemistry contribution within PubChem is provided under a CC-BY-NC-ND 4.0 license, unless otherwise stated.
    https://creativecommons.org/licenses/by-nc-nd/4.0/
  55. USGS Health-Based Screening Levels for Evaluating Water-Quality Data
  56. Wikidata
  57. Wikipedia
  58. Wiley
  59. Medical Subject Headings (MeSH)
    LICENSE
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    https://www.nlm.nih.gov/copyright.html
    Cytochrome P-450 CYP2C8 Inhibitors
    https://www.ncbi.nlm.nih.gov/mesh/68065687
    Anti-Infective Agents, Urinary
    https://www.ncbi.nlm.nih.gov/mesh/68000892
  60. PubChem
  61. GHS Classification (UNECE)
  62. EPA Substance Registry Services
  63. MolGenie
    MolGenie Organic Chemistry Ontology
    https://github.com/MolGenie/ontology/
  64. PATENTSCOPE (WIPO)
  65. NCBI
CONTENTS