Trimethoprim

290.31800

290.32

212-006-2

AN164J8Y0X

757370|752719|106568

2811

DTXSID3023712

C908

White to cream, crystalline powder

J01EE01|J - Antiinfectives for systemic use

2933599090

105.51000

0.9

Trimethoprim is an odorless white powder. Bitter taste. (NTP, 1992)

1.252 g/cm3

199-203 °C

526ºC at 760 mmHg

271.9ºC

1.600

<0.1 g/100 mL at 24 ºC

2-8ºC

LD50 orally in mice: 7000 mg/kg (Yamamoto)

Odorless

Bitter

7.12(at 20 °C)

7.12 (at 20 °C)|pKa= 7.12 (conjugate acid)

170.8 Ų [M+H]+ [CCS Type: TW, Method: Major Mix IMS/Tof Calibration Kit (Waters)]|171.2 Ų [M+H]+ [CCS Type: TW, Method: calibrated with polyalanine and drug standards]|172.89 Ų [M+H]+

Insoluble in water.

Amines, Phosphines, and Pyridines

This compound readily forms salts with acids. (NTP, 1992).

III

6.1(b)

UN 3249

3

R25

S45

UV8225000

T

Stable. Incompatible with strong oxidizing agents, acids.

P201, P202, P260, P263, P264, P270, P273, P281, P301+P310, P308+P313, P314, P321, P330, P391, P405, P501

H301

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.

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).|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/|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/|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/|For more FDA Requirements (Complete) data for TRIMETHOPRIM (7 total), please visit the HSDB record page.

Flash point data for this chemical are not available. It is probably combustible. (NTP, 1992)

|Danger|H302 (92.8%): Harmful if swallowed [Warning Acute toxicity, oral]|P201, P202, P260, P264, P270, P273, P281, P301+P312, P308+P313, P314, P330, P391, P405, and P501|Aggregated GHS information provided by 135 companies from 20 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.|H301: Toxic if swallowed [Danger Acute toxicity, oral]|P201, P202, P260, P263, P264, P270, P273, P281, P301+P310, P308+P313, P314, P321, P330, P391, P405, and P501

Fires involving this material can be controlled with a dry chemical, carbon dioxide or Halon extinguisher. (NTP, 1992)

Excerpt from ERG Guide 154 [Substances - Toxic and/or Corrosive (Non-Combustible)]: As an 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, in the downwind direction, as necessary, the isolation distance shown above. FIRE: If tank, rail car or tank truck 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, 2016)

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)

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)

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).

The oral LD50 in mice and rats is 2764 mg/kg and >5300 mg/kg, respectively. Prescribing information for trimethoprim states that signs of overdose may be evident following ingestion of doses >1 gram, and may include nausea, vomiting, dizziness, headaches, mental depression, confusion, and bone marrow depression. Treatment should consist of general supportive measures and gastric lavage, if applicable. Urinary acidification may increase renal elimination of trimethoprim. Hemodialysis is only moderately effective in eliminating trimethoprim and peritoneal dialysis is of no benefit.

TMP-SMZ causes a characteristic idiosyncratic liver injury that has features of drug-allergy or hypersensitivityand that resembles the injury attributable to the sulfonamides. The typical onset is sudden development of fever and rash followed by jaundice within a few days or weeks of starting the medication. Eosinophilia or atypical lymphocytosis are also common. The pattern of injury is typically cholestatic or mixed and can be complicated and prolonged. As with other sulfonamides, TMP-SMZ has been linked to cases of hepatocellular injury that can be severe and lead to acute liver failure. In most recent case series, TMP-SMZ has ranked within the top 5 to 10 causes of drug induced, idiosyncratic fulminant hepatic failure. However, most cases resolve rapidly, usually within 2 to 4 weeks unless cholestasis is severe. TMP-SMZ can also cause mild elevations in ALT levels that do not proceed to more severe liver injury or jaundice, and may be accompanied by hepatic granulomas.

Concomitant admin of trimethoprim or trimethoprim/sulfamethoxazole with methotrexate may incr bone marrow suppression, probably as an additive antifolate effect.|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.|Trimethoprim may inhibit the metab of phenytoin, increasing the half-life of phenytoin by up to 50% & decreasing its clearance by 30%.|Concurrent use /with rifampin/ may significantly increase the elimination and shorten the elimination half-life of trimethoprim.|For more Interactions (Complete) data for TRIMETHOPRIM (15 total), please visit the HSDB record page.

LD50 Mice oral 7000 mg/kg|LD50 Rat oral 200 mg/kg|LD50 Mouse oral 3960 mg/kg|LD50 Mouse ip 1870 mg/kg|LD50 Mouse iv 200 mg/kg

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

Trimethoprim's production and use as an antibiotic(1,2) may result in its release to the environment through various waste streams(SRC).

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).|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).|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).

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).

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).

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).

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).

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).

Trimethoprim is distributed into milk in concentrations approximately 125% those of concurrent maternal serum concentrations.|Trimethoprim is excreted into breast milk in low concns.

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)

Trimethoprim is distributed into milk in concentrations approximately 125% those of concurrent maternal serum concentrations.

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.|FDA Label

Sulfamethoxazole with trimethoprim is a fixed antibiotic combination that is widely used for mild-to-moderate bacterial infections and as prophylaxis against opportunistic infections. Like other sulfonamide-containing medications, this combination has been linked to rare instances of clinically apparent acute liver injury.

Antiinfective Agents

Anti-Infective Agents, Urinary; Antimalarials; Antimetabolites; Folic Acid Antagonists|Trimethoprim given alone has also been effective for urinary tract infections, but the development of resistant organisms limits the usefulness of this treatment.|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/|trimethoprim is used in the prophylaxis of bacterial urinary tract infections. /NOT included in US product labeling/|For more Therapeutic Uses (Complete) data for TRIMETHOPRIM (8 total), please visit the HSDB record page.

Because trimethoprim may interfere with folic acid metabolism, the drug should be used with caution in nursing women.|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.|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.|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.|For more Drug Warnings (Complete) data for TRIMETHOPRIM (28 total), please visit the HSDB record page.

Most gram-negative and gram-positive microorganisms are sensitive to trimethoprim, but resistance can develop when the drug is used alone.|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.

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.

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.)|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.)|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.)|Substances capable of killing agents causing urinary tract infections or of preventing them from spreading. (See all compounds classified as Anti-Infective Agents, Urinary.)|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.)

Steady-state concentrations are achieved after approximately 3 days of repeat administration. Average peak serum concentrations of approximately 1 µg/mL (C_max) are achieved within 1 to 4 hours (T_max) 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.|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.|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.|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.|Only small amounts of trimethoprim are excreted in feces via biliary elimination. Trimethoprim may be moderately removed by hemodialysis.|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.|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.|For more Absorption, Distribution and Excretion (Complete) data for TRIMETHOPRIM (12 total), please visit the HSDB record page.

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 ... .|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).

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.

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.|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.

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)

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)

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.|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.|/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/|/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/

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 ... .|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.|Single case report of Niikawa-Kuroki syndrome (mental & physical growth retardation & craniofacial anomalies) in non-Japanese girl.|Trimethoprim poisoning has been characterized by nausea, vomiting, headache, swollen face, epigastric pain, & weakness.|For more Human Toxicity Excerpts (Complete) data for TRIMETHOPRIM (11 total), please visit the HSDB record page.

Proloprim

Preparations: Tablets, 100 and 200 mg.|Component of Bactrin and Septra

See sulfamethoxazole, sulfadiazine, sulfametrole, sulfamoxole, and sulfalene for list of trade names of mixtures with trimethoprim.|Authorized or allowed for use in aquaculture in certain European countries.|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.

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.|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%.

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.|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.

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