| Size | Price | |
|---|---|---|
| 500mg | ||
| 1g | ||
| Other Sizes |
| Targets |
DHFR/Dihydrofolate reductase; Influenza A virus
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|---|---|
| ln Vitro |
By preventing dihydrofolate reductase (DHFR) from functioning, trimethoprim disrupts the metabolism of folate and converts dihydrofolate to tetrahydrofolate (THF) [1]. In E. coli, trimethoprim (3 μg/mL; 1 h) causes significant heat shock proteins (Hsps) and protein aggregation. coli cells, indicating that protein misfolding is brought on by trimethoprim sulfate [1]. E. coli produces DnaK, DnaJ, GroEL, ClpB, and IbpA/B Hsps when treated with trimethoprim (1.5–3 μg/mL; 1 hour). Coli cells subjected to heat stress and folate [1].
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| ln Vivo |
Trimethoprim (10 mg/kg; IV; every 12 hours; 3 days) demonstrated antibacterial activity against Neisseria meningitidis, Escherichia coli, Haemophilus influenzae, and Streptococcus pneumoniae in infected mice[2]. Trimethoprim has a half-life of about an hour in full serum and a MIC value of about 1 μM against E. coli. It can be associated with thiomaltose (TM-TMP) and shows stability. Coli [2]. The injection of trimethoprim-zinc mixed suspension (10 mg/mL; 0.5 mL) lowers virus titers and increases the survival rate of chicken embryos [4].
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| Enzyme Assay |
Influenza virus was isolated from patients and propagated in eggs. We determined viral load that infects 50% of eggs (50% egg lethal dose, ELD50). We introduced 10 ELD50 into embryonated eggs and repeated the experiments using 100 ELD50. A mixture of zinc oxide (Zn) and trimethoprim (TMP) (weight/weight ratios ranged from 0.01 to 0.3, Zn/TMP with increment of 0.1) was tested for embryo survival of the infection (n = 12 per ratio, in triplicates). Embryo survival was determined by candling eggs daily for 7 days. Controls of Zn, TMP, saline or convalescent serum were conducted in parallel. The effect of Tri-Z on virus binding to its cell surface receptor was evaluated in a hemagglutination inhibition (HAI) assay using chicken red cells. Tri-Z was prepared to concentration of 10 mg TMP and 1.8 mg Zn per ml, then serial dilutions were made. HAI effect was expressed as scores where ++++ = no effect; 0 = complete HAI effect.
Results: TMP, Zn or saline separately had no effect on embryo survival, none of the embryos survived influenza virus infection. All embryos treated with convalescent serum survived. Tri-Z, at ratio range of 0.15-0.2 (optimal ratio of 0.18) Zn/TMP, enabled embryos to survive influenza virus despite increasing viral load (> 80% survival at optimal ratio). At concentration of 15 µg/ml of optimal ratio, Tri-Z had total HAI effect (scored 0). However, at clinical concentration of 5 µg/ml, Tri-Z had partial HAI effect (+ +). Conclusion: Acting on host cells, Tri-Z at optimal ratio can reduce the lethal effect of influenza A virus in chick embryo. Tri-Z has HAI effect. These findings suggest that combination of trimethoprim and zinc at optimal ratio can be provided as treatment for influenza and possibly other respiratory RNA viruses infection in man.[1] |
| Cell Assay |
Trimethoprim (TMP), an inhibitor of dihydrofolate reductase, decreases the level of tetrahydrofolate supplying one-carbon units for biosynthesis of nucleotides, proteins, and panthotenate. We have demonstrated for the first time that one of the effects of the TMP action in E. coli cells is protein aggregation and induction of heat shock proteins (Hsps). TMP caused induction of DnaK, DnaJ, GroEL, ClpB, and IbpA/B Hsps. Among these Hsps, IbpA/B were most efficiently induced by TMP and coaggregated with the insoluble proteins. Upon folate stress, deletion of the delta ibpA/B operon resulted in increased protein aggregation but did not influence cell viability.[1]
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| Animal Protocol |
Animal/Disease Models: Female C3H/HeOuJ mice (transurethral infection in 50 μL suspension containing 1-2×107 CFU E. coli under 3% isoflurane) [2]
Doses: 10 mg/kg Route of Administration: intravenous (iv) (iv)injection ; Once every 12 hrs (hrs (hours)); 3 days Experimental Results:Antibacterial activity against Haemophilus influenzae, Streptococcus pneumoniae, Escherichia coli and Neisseria meningitidis. The CD50 of the infected person was 150 mg/kg, 335 mg/kg, 27.5 respectively. mg/kg and 8.4 mg/kg mice. Animal/Disease Models: Fertilized eggs (H3N2 virus is injected into the amniotic membrane and allantoic cavity on day 8) [4] Doses: 10 mg/mL; 0.5 mL Route of Administration: Trimethoprim-zinc composite suspension is injected into the air sac; single dose Experimental Results: The virus titer was diminished and the survival rate of chicken embryos was improved. Survival rates peaked at a ratio of approximately 0.18 (Zn/trimethoprim). |
| ADME/Pharmacokinetics |
Absorption
Steady-state plasma concentrations are reached approximately 3 days after repeated administration. Following a single 100 mg dose, the mean peak serum concentration (Cmax) is reached within 1 to 4 hours (Tmax), approximately 1 µg/mL. The pharmacokinetics of trimethoprim appear to follow first-order kinetics; after a single 200 mg dose, serum concentrations are approximately twice that of the 100 mg dose. The steady-state AUC of oral trimethoprim is approximately 30 mg/L·h. Elimination Route Approximately 10-20% of the ingested dose of trimethoprim is metabolized, primarily in the liver, with the remainder largely excreted unchanged in the urine. Following oral administration, 50% to 60% of trimethoprim is excreted in the urine within 24 hours, of which approximately 80% is the unchanged drug. Volume of Distribution After oral administration, trimethoprim is widely distributed in various tissues. It is well distributed in sputum, middle ear effusion, and bronchial secretions. Trimethoprim is efficiently distributed in vaginal secretions at concentrations approximately 1.6 times higher than its serum concentration. It can cross the placental barrier and enter breast milk. Trimethoprim is also readily excreted in feces, significantly reducing and/or eliminating fecal flora sensitive to it. Clearance Renal clearance of trimethoprim after oral administration varies, ranging from 51.7 to 91.3 mL/min. Trimethoprim is widely distributed in tissues and fluids throughout the body, including aqueous humor, middle ear fluid, saliva, lung tissue, sputum, semen, prostate tissue and fluid, vaginal secretions, bile, bones, and cerebrospinal fluid. The apparent volume of distribution of trimethoprim in adults with normal renal function is 100–120 liters. …The binding rate of trimethoprim to plasma proteins is 42–46%. Trimethoprim readily crosses the placenta; its concentration in amniotic fluid has been reported to be approximately 80% of the maternal serum concentration. Only a small amount of trimethoprim is excreted in the bile and feces. Hemodialysis can partially remove trimethoprim. Trimethoprim is readily absorbed from the gastrointestinal tract and is almost completely absorbed. After a single oral dose of 100 mg, 160 mg, and 200 mg of trimethoprim, the peak serum concentrations within 1–4 hours are approximately 1 μg/mL, 1.6 μg/mL, and 2 μg/mL, respectively. After multiple oral doses, the steady-state peak serum concentration of trimethoprim is typically 50% higher than that after a single dose. In adults with normal renal function, the steady-state serum concentration range after an oral dose of 160 mg of trimethoprim every 12 hours is 1.2–3.2 μg/mL. Trimethoprim is rapidly and widely distributed in various tissues and fluids, including the kidneys, liver, spleen, bronchial secretions, saliva, and semen. Trimethoprim is also present in bile and aqueous humor; bone marrow and cancellous bone, but not compact bone. View MoreMetabolism/Metabolites Biological Half-Life The half-life of trimethoprim is 8-10 hours, but may be prolonged in patients with renal insufficiency. In adults with normal renal function, the serum half-life of trimethoprim is approximately 8-11 hours. In adults with creatinine clearance of 10–30 ml/min or 0–10 ml/min, the serum half-life of this drug may be prolonged to 15 hours or >26 hours, respectively. It has been reported that the serum half-life of trimethoprim is approximately 7.7 hours in children under 1 year of age and approximately 5.5 hours in children aged 1 to 10 years. |
| Toxicity/Toxicokinetics |
Effects during pregnancy and lactation
◉ Overview of medication use during lactation Due to the low levels of trimethoprim in breast milk, the amount ingested by infants is very small, and no adverse effects are expected on breastfed infants. ◉ Effects on breastfed infants In one study, no adverse reactions were observed in infants 4 days after mothers took trimethoprim-sulfamethoxazole. In a telephone follow-up study, 12 lactating mothers reported taking trimethoprim-sulfamethoxazole (dosage not specified). Two of these mothers reported feeding difficulties in their infants. No diarrhea was reported in exposed infants. ◉ Effects on lactation and breast milk As of the revision date, no relevant published information was found. Drug interactions Concomitant use of trimethoprim or trimethoprim/sulfamethoxazole with methotrexate may increase myelosuppression, possibly due to the additive antifolate effects. Concomitant use of trimethoprim or between courses of treatment with other folic acid antagonists (such as methotrexate or pyrimethamine) is not recommended, as it may increase the incidence of megaloblastic anemia. Trimethoprim may inhibit the metabolism of phenytoin, prolonging its half-life by up to 50% and reducing its clearance by 30%. Non-human toxicity values Oral LD50 in mice: 7000 mg/kg Oral LD50 in rats: 200 mg/kg Oral LD50 in mice: 3960 mg/kg Protein binding Trimethoprim binds to 44% of plasma proteins, but the specific proteins it binds to have not been identified. |
| References |
|
| Additional Infomation |
See also: Trimethoprim (with active ingredient).
|
| Molecular Formula |
C14H18N4O3.HCL
|
|---|---|
| Molecular Weight |
326.77866
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| Exact Mass |
326.115
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| CAS # |
60834-30-2
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| Related CAS # |
Trimethoprim;738-70-5;Trimethoprim lactate;23256-42-0;Trimethoprim-d3;1189923-38-3;Trimethoprim sulfate;56585-33-2;Trimethoprim-13C3;1189970-95-3
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| PubChem CID |
173769
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| Appearance |
Typically exists as solid at room temperature
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| Boiling Point |
526ºC at 760 mmHg
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| Flash Point |
271.9ºC
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| LogP |
1.919
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| Hydrogen Bond Donor Count |
3
|
| Hydrogen Bond Acceptor Count |
7
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| Rotatable Bond Count |
5
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| Heavy Atom Count |
22
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| Complexity |
307
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| Defined Atom Stereocenter Count |
0
|
| SMILES |
Cl.COC1=CC(CC2=CN=C(N)N=C2N)=CC(OC)=C1OC
|
| InChi Key |
YLCCEQZHUHUYPA-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C14H18N4O3.ClH/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);1H
|
| Chemical Name |
5-[(3,4,5-trimethoxyphenyl)methyl]pyrimidine-2,4-diamine;hydrochloride
|
| Synonyms |
TRIMETHOPRIM HYDROCHLORIDE; Trimethoprim HCl; Trimplex; Primsol; 60834-30-2; Trimplex 200; UNII-9XE000OU9B; 9XE000OU9B;
|
| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples
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|---|---|
| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 3.0602 mL | 15.3008 mL | 30.6016 mL | |
| 5 mM | 0.6120 mL | 3.0602 mL | 6.1203 mL | |
| 10 mM | 0.3060 mL | 1.5301 mL | 3.0602 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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