Ferredoxin system and low oxidation-reduction potential that mediate the reduction of the 5-nitro group to reactive intermediates; the reduction products are responsible for antimicrobial activity. [1]
Resistance in Bacteroides fragilis is associated with decreased nitro-reductase activity and lowered dehydrogenase activity. [1]
Resistance in Trichomonas vaginalis is linked to oxygen interference with drug action under aerobic conditions, but not under anaerobic conditions. [1]

Among the most potent antibacterial agents against the most drug-resistant anaerobic bacteria, Bacteroides fragilis, is tinidazole. Giardiasis, amebiasis, and trichomonal vaginitis are among the protozoal infections that tinidazole is effective against [1].

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Tinidazole is bactericidal at low concentrations against anaerobic bacteria and protozoa. Its spectrum covers most anaerobic bacteria and some capnophilic microorganisms. Anaerobic bacteria known to be resistant include anaerobic streptococci, Actinomyces, and Propionibacteria. [1]
Against Bacteroides fragilis (one of the most resistant anaerobic species), only a few resistant strains have been reported. [1]
Minimum inhibitory concentration (MIC) values for >90% of tested strains of Bacteroides, Fusobacterium, and Clostridium spp. are less than 4 mg/L. Table 1 provides detailed MIC distribution: for B. fragilis (100 strains), 3 strains at 0.125 mg/L, 3 at 0.25, 4 at 0.5, 4 at 1.0, 2 at 2.0, 3 at 4.0, and 0 at ≥8.0; for Bacteroides species (40 strains), 6 at ≤0.125, 10 at 0.25, 17 at 0.5, 4 at 1.0, 3 at 2.0; for Fusobacterium species (40 strains), 4 at ≤0.125, 2 at 0.25, 4 at 1.0, 11 at 2.0, 1 at 4.0; for Clostridium species (60 strains), 7 at ≤0.125, 10 at 0.25, 2 at 0.5, 3 at 1.0, 11 at 2.0, 15 at 4.0, 4 at ≥8.0; for Peptococci/Peptostreptococci (85 strains), 8 at ≤0.125, 17 at 0.25, 14 at 0.5, 19 at 1.0, 37 at 2.0, 17 at 4.0. [1]
Actinomyces, Arachnia, and Propionibacteria are resistant. Microaerophilic streptococci and anaerobic streptococci are resistant, while Peptococci and Peptostreptococci are sensitive. Some capnophilic bacteria such as Gardnerella vaginalis and Campylobacter fetus are susceptible. [1]
Aerobic bacteria (streptococci, staphylococci, enterobacteriaceae) are usually highly resistant. However, when E. coli, Klebsiella, or Proteus are grown under reduced conditions, activity is enhanced. Some aerobes like Bacillus and Moraxella are susceptible. [1]
Tinidazole has a rapid onset of bactericidal activity against B. fragilis as shown by time-kill curves; bactericidal rates are not affected by inoculum size, nutritional requirements, or growth rate. [1]

In an experimental rat model of intra-abdominal sepsis (simulating peritonitis), systemic administration of Tinidazole alone reduced mortality to 22% within 4 days, compared to 43% for clindamycin alone and 46% for netilmicin alone. Combination of tinidazole with netilmicin reduced mortality to 5%. [1]
When tinidazole was given locally (intraperitoneally) just before closing the abdominal wall, 40% of animals died of acute peritonitis; surviving animals developed multiple abscesses and advanced adhesions. [1]
Oral tinidazole (150 mg every 12 h for 7 days) caused only a slight decrease in oral/throat fusobacteria; no significant changes in colon microflora. A single 1 g oral dose markedly decreased oral aerobic and anaerobic bacteria, with normalization within 14 days. Intravenous tinidazole (800 mg initial then 400 mg every 12 h for 2 days) caused significant changes in colon microflora: enterococci and streptococci proliferated; cocci, gram-positive rods, fusobacteria, and bacteroides decreased. Measurable fecal concentrations were found only in 7 patients, but mucous tissue concentrations (0.7-18.2 mg/kg) were observed in all patients. Microflora normalized after 2 weeks. [1]

Intra-abdominal sepsis model in rats: A 1 cm segment of the ileum was isolated, intestinal continuity was re-established by end-to-end anastomosis, and the ileal segment was returned to the abdominal cavity. Mortality rate, abscess formation, and intra-abdominal adhesions were recorded. [1]
Systemic administration: Tinidazole was given systemically alone or in combination with netilmicin. The specific doses and routes for rats are not explicitly stated, but the study compared tinidazole, clindamycin, and netilmicin. [1]
Local administration: Tinidazole was given locally just before closing the abdominal wall. [1]

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Intra-abdominal sepsis model in rats: A 1 cm segment of the ileum was isolated, intestinal continuity was re-established by end-to-end anastomosis, and the ileal segment was returned to the abdominal cavity. Mortality rate, abscess formation, and intra-abdominal adhesions were recorded. [1]
Systemic administration: Tinidazole was given systemically alone or in combination with netilmicin. The specific doses and routes for rats are not explicitly stated, but the study compared tinidazole, clindamycin, and netilmicin. [1]
Local administration: Tinidazole was given locally just before closing the abdominal wall. [1]

Absorption, Distribution and Excretion
Tinidazole is rapidly and completely absorbed on an empty stomach. Taking it with food delays the time to peak concentration (Tmax) by approximately 2 hours and decreases the peak concentration (Cmax) by approximately 10%, with an AUC of 901.6 ± 126.5 mcg·hr/mL. Tinidazole can cross the placental barrier and is secreted into breast milk. It is excreted via the liver and kidneys. Tinidazole is primarily excreted unchanged in the urine (approximately 20-25% of the administered dose). Approximately 12% is excreted in the feces. Tinidazole is distributed in almost all tissues and body fluids. It can also cross the blood-brain barrier and placental barrier and is secreted into breast milk. Volume of distribution (VolD): Approximately 50 liters. Tinidazole is rapidly and completely absorbed on an empty stomach. Taking it with food delays the time to peak concentration (Tmax) by approximately 2 hours and decreases the peak concentration (Cmax) by approximately 10%, with an AUC of 901.6 ± 126.5 μg·h/mL.
Time to peak concentration: 1.6 (± 0.7) hours.
Excretion: Renal: 20% to 25% excreted unchanged. Fecal: 12%. Hemodialysis: 43% cleared during 6 hours of hemodialysis.
For more complete data on absorption, distribution, and excretion of tinidazole (6 items), please visit the HSDB record page.
Metabolism/Metabolites

Hepatic metabolism, primarily via CYP3A4. Similar to metronidazole, tinidazole is largely metabolized and excreted in the body. Tinidazole is partially metabolized through oxidation, hydroxylation, and conjugation. Tinidazole is the main drug component in plasma after treatment, in addition to a small amount of 2-hydroxymethyl metabolite. Tinidazole is primarily biotransformed via CYP3A4. In an in vitro drug interaction study, tinidazole at concentrations up to 75 μg/mL did not inhibit the enzyme activities of CYP1A2, CYP2B6, CYP2C9, CYP2D6, CYP2E1, and CYP3A4.
Biological Half-Life
The elimination half-life is 13.2 ± 1.4 hours, and the plasma half-life is 12 to 14 hours.
Elimination: 13.2 (± 1.4) hours. Plasma: Approximately 12 to 14 hours.

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Half-life of Tinidazole is 12.7 h (one-compartment model). [1]
After oral doses of 2000 mg and intravenous doses of 800-1600 mg, pharmacokinetic properties are similar; antimicrobial plasma concentrations permit once-daily dosing. Concentrations are the same in serum and plasma. [1]
Intravenous study: Five daily infusions of 800 mg (13 min each). After Day 1 infusion, concentrations declined with first-order kinetics. Subsequent daily infusions caused small increases in pre- and post-dose concentrations. At end of Day 2, mean concentrations exceeded 5 mg/L at 24 h post-infusion; peak plasma concentrations ~20 mg/L. [1]
Oral study: 2 g on Day 1, then 1 g daily at 24 h intervals. Plasma detectable at 0.5 h; peak concentrations at 0.5-2 h (most frequently 2 h). Mean peak plasma concentration Day 1: males 40.0 mg/L, females 57.6 mg/L. Before Day 2 dose: males 11.3 mg/L, females 16.2 mg/L. After dose reduction to 1 g, pre-dose levels on Days 3-5 somewhat lower than Day 2. On Day 5, peak concentrations: males 26.3 mg/L, females 36.2 mg/L. Oral bioavailability >90% (essentially complete). [1]
Metabolism: In rats/dogs, urinary excretion accounts for about two-thirds of oral and IV doses; about half of excreted drug is unchanged, remainder is 2-hydroxyethyl derivative, its glucuronide conjugate, and two other unidentified metabolites. In humans, after single IV 1600 mg, ~25% recovered unchanged in urine; hydroxyethyl metabolite and its glucuronide account for ~2%; another metabolite accounts for ~10%. Renal clearance 12 mL/min (about one-quarter of total plasma clearance). [1]
Distribution: Widely distributed in animal tissues. In rats, highest concentrations at 2 h; cecum and large intestine >2x blood levels. At 24 h, kidneys, liver, stomach >2x blood. In dogs, eyes and gall bladder >2x blood at end of infusion; at 6 h kidneys and liver similar. In humans, secreted in saliva (concentrations similar to serum). In gynecological patients after 2 g oral, genital tract concentrations 50-100% of serum. Bile concentrations similar to serum at 12 h. After IV 800 mg pre-surgery, peak serum 12.3-51.7 mg/L; intestinal mucous tissue concentrations 6.0-18.2 mg/L at 0.5-2 h in half of patients. After IV 1600 mg, abdominal tissue concentrations 60-120% of serum. Cerebrospinal fluid concentrations 17-39 mg/L at 1.5 h after 2 g oral. Milk concentrations 5.8-12.7 mg/L (mean milk/serum ratio 1.62). [1]

Hepatotoxicity
Tinidazole is typically taken for only a few days, but its use has been reported to cause elevated serum enzymes, and elevated serum enzymes during treatment are listed as a possible adverse event on product labels. Tinidazole may also cause allergic reactions, including urticaria, angioedema, and bronchospasm, which may be accompanied by mild elevations in serum enzymes. Although tinidazole is widely used globally, there is no conclusive evidence that it is associated with clinically significant liver injury with jaundice. Probability Score: E (Suspected but unconfirmed rare clinically significant cause of liver injury) Pregnancy and Lactation Effects ◉ Overview of Use During Lactation Tinidazole levels in breast milk are lower than the dose given to the infant. There are no reports of measurements of plasma drug concentrations in infants during breastfeeding. No studies have evaluated adverse reactions of tinidazole in infants during lactation, but it is speculated that adverse reactions are similar to those of the closely related drug metronidazole, such as an increased risk of oral and rectal candidiasis. Similar to metronidazole, there are concerns about healthy infants being exposed to tinidazole through breast milk, as tinidazole may be mutagenic and carcinogenic. Experts disagree on the benefits and risks of long-term use of tinidazole during breastfeeding, but avoiding breastfeeding for 3 days after a single dose should reduce the drug concentration in breast milk to a negligible level. Other medications used to treat bacterial vaginosis can be administered vaginally, thus reducing the drug concentration in breast milk.
◉ Effects on breastfed infants
No published information found as of the revision date.
◉ Effects on lactation and breast milk
No published information found as of the revision date.

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Protein binding
Tinidazole has a plasma protein binding rate of 12%.

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Interactions
Cholestyramine may reduce oral bioavailability; it is recommended to take cholestyramine and tinidazole separately.
When these medications (coumarin anticoagulants) are used concomitantly with tinidazole, their effects may be enhanced, leading to prolonged prothrombin time; the dosage of oral anticoagulants may need to be adjusted during tinidazole treatment and for up to 8 days after discontinuation.
It is recommended not to use these substances (ethanol, ethanol-containing preparations, propylene glycol) concomitantly with tinidazole, or within 3 days after the end of tinidazole treatment; abdominal cramps, nausea, vomiting, headache, or flushing may occur.
Concomitant use of intravenous phenytoin sodium or fosetyl-p-ethyl sodium with tinidazole will prolong the half-life of phenytoin sodium and reduce its clearance.
For more complete data on interactions of tinidazole (11 types), please visit the HSDB record page.

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Non-human toxicity values
Acute LD50 in mice > 3,600 mg/kg
Intraperitoneal LD50 in mice > 2,300 mg/kg
Oral LD50 in rats > 2,000 mg/kg
Intraperitoneal LD50 in rats > 2,000 mg/kg

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Tinidazole is generally well tolerated. Adverse reactions include minor disturbances: mild diarrhea, vomiting, nausea, metallic taste, rash, and thrombophlebitis after intravenous administration. No serious toxicity or dose-limiting side effects reported at recommended doses (e.g., 2000 mg oral, 800-1600 mg IV). [1]

[1]. Tinidazole--microbiology, pharmacology and efficacy in anaerobic infections. Infection. 1983;11(1):54-60.

Tinidazole is a 1H-imidazol derivative with a (2-ethylsulfonyl)ethyl substituted at the C-1 position, a methyl substituted at the C-2 position, and a nitro substituted at the C-5 position. It is an antiprotozoal and antibacterial drug. It possesses antiprotozoal, antibacterial, antiparasitic, and anti-amoebic pharmacological activities. Tinidazole is a nitroimidazole antitrichomonal drug, effective against Trichomonas vaginalis, Entamoeba histolytica, and Giardia lamblia infections. Tinidazole is a nitroimidazole antibacterial drug. Tinidazole is an oral broad-spectrum antibacterial drug used to treat bacterial, protozoan, and parasitic infections. Tinidazole is a nitroimidazole drug, similar to metronidazole, and its side effect spectrum and frequency may also be similar, including a low incidence of elevated serum enzymes during treatment and rare clinically significant acute liver injury. Tinidazole is a 5-nitroimidazole derivative with antiprotozoal activity. Although its mechanism of action is not fully understood, studies have shown that tinidazole is metabolized to produce nitrite anions and metronidazole. The nitro group of metronidazole is reduced by the parasite's ferredoxin, resulting in a series of free nitro groups, including nitro anions. Its toxicity is achieved by consuming sulfhydryl groups and causing DNA strand breaks; repeated damage has a cumulative effect, ultimately leading to cell death. Tinidazole is a nitroimidazole alkylating agent used as an antitrichomonal drug to treat infections caused by parasites such as Trichomonas vaginalis and Entamoeba histolytica, as well as Giardia lamblia infections. It is also used as an antibacterial agent to treat bacterial vaginosis and anaerobic bacterial infections. Drug Indications: It is used to treat trichomoniasis in men and women caused by Trichomonas vaginalis. It is also used to treat Giardiasis in adults and children over three years of age caused by Giardia duodenalis, and intestinal amebiasis and amebic liver abscess in adults and children over three years of age caused by Entamoeba histolytica.
FDA Label

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Mechanism of Action
Tinidazole is a prodrug and antiprobiotic agent. The nitro group of tinidazole is reduced in Trichomonas vaginalis via a ferredoxin-mediated electron transport system. The free nitro groups generated from this reduction reaction are considered the source of antiprobiotic activity. Studies have shown that these toxic free radicals covalently bind to DNA, causing DNA damage and ultimately leading to cell death. The mechanism of action of tinidazole against Giardia lamblia and Entamoeba histolytica is unclear, but may be similar.
The nitro group of tinidazole can be reduced by Trichomonas vaginalis cell extracts. The free nitro groups generated from this reduction reaction may be the source of antiprobiotic activity. The mechanism of action of tinidazole against Giardia lamblia and Entamoeba histolytica is unclear.

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Therapeutic Uses
Antitrichomoniasis
Drug: Antibiotics for animals (Trichomonas, Giardia); Anti-amoebic; Antibacterial
Oral tinidazole is indicated for the treatment of amoebic liver abscess caused by Entamoeba histolytica, in adults and children aged three years and older. /US Product Label Includes/
Oral tinidazole is indicated for the treatment of intestinal amebiasis caused by Entamoeba histolytica, in adults and children aged three years and older. /US Product Label Includes/
For more complete data on the therapeutic uses of tinidazole (6 types), please visit the HSDB record page.

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Drug Warnings
Tinidazole can be distributed into breast milk at concentrations similar to those in serum. Because tinidazole can be detected in breast milk for up to 72 hours after administration, breastfeeding is recommended to be discontinued during tinidazole treatment and for three days after the last dose.
FDA Pregnancy Risk Class: C / Risk cannot be ruled out. Currently, adequate, well-controlled human studies are lacking, and animal studies have either not shown any risk to the fetus or lack relevant data. Taking this drug during pregnancy may cause harm to the fetus; however, the potential benefits may outweigh the potential risks. Tinidazole can cross the placenta and enter fetal circulation. Therefore, pregnant women should not take this product during early pregnancy. Adverse reactions occurring in ≥1% of patients taking tinidazole include gastrointestinal reactions (metallic/bitter taste, nausea, anorexia, indigestion/cramps/upper abdominal discomfort, vomiting, constipation) and neurological reactions (asthenia/fatigue/malaise, dizziness, headache). For more complete data on tinidazole (11 in total), please visit the HSDB record page.

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Pharmacodynamics
Tinidazole is a synthetic antiprotozoal drug. Tinidazole has shown activity against the following protozoa in vitro and in clinical infections: Trichomonas vaginalis, Giardia lamblia (also known as Giardia lanciole), and Entamoeba histolytica. Tinidazole appears to have no activity against most vaginal lactobacillus strains.

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Mechanism of action: Tinidazole has low molecular weight and penetrates cell membranes of both aerobes and anaerobes. Anaerobes have higher uptake. Accumulation is mediated by reduction of the molecule to reactive intermediates at the 5-nitro group via a ferredoxin system and low oxidation-reduction potential. Aerobes do not generate low oxidation-reduction potentials, explaining selective activity. [1]
Clinical efficacy: Effective in protozoal infections (trichomonal vaginitis, amoebiasis, giardiasis). Effective in anaerobic infections including respiratory tract infections, intra-abdominal sepsis, obstetric and gynecological infections. No activity against aerobes, so must be combined with other antibacterials for mixed infections. [1]
Prophylaxis: Effective in preventing postoperative infections following colorectal surgery, emergency appendectomy, gynecological surgery, elective colonic and abdominal surgery. Single IV dose of 1600 mg or oral 2 g significantly reduces infection rates (e.g., wound infections from ~40% to 7%). [1]
Cross-resistance: Metronidazole-resistant strains of B. fragilis and T. vaginalis show cross-resistance to tinidazole in vitro. [1]
Clinical treatment results: In intra-abdominal infections (72 cases), 82% satisfactory response. In obstetric/gynecological infections, ~89% cure rate. In septicaemia (14 patients), rapid clinical cure in 12 after IV tinidazole. [1]

C8H13N3O4S

247.2715

247.062

19387-91-8

Tinidazole-d5;1216767-04-2

5479

White to off-white solid powder

1.4±0.1 g/cm3

528.4±30.0 °C at 760 mmHg

117-121 °C(lit.)

273.4±24.6 °C

0.0±1.3 mmHg at 25°C

1.599

-0.27

0

5

4

16

345

0

S(C([H])([H])C([H])([H])[H])(C([H])([H])C([H])([H])N1C(=C([H])N=C1C([H])([H])[H])[N+](=O)[O-])(=O)=O

HJLSLZFTEKNLFI-UHFFFAOYSA-N

InChI=1S/C8H13N3O4S/c1-3-16(14,15)5-4-10-7(2)9-6-8(10)11(12)13/h6H,3-5H2,1-2H3

1-(2-ethylsulfonylethyl)-2-methyl-5-nitroimidazole

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ≥ 50 mg/mL (~202.21 mM)
H2O : ~3.33 mg/mL (~13.47 mM)

Solubility in Formulation 1: ≥ 3.25 mg/mL (13.14 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 32.5 mg/mL clear DMSO stock solution to 400 μL of PEG300 and mix evenly; then add 50 μL of Tween-80 to the above solution and mix evenly; then add 450 μL of normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 3.25 mg/mL (13.14 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 32.5 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 3.25 mg/mL (13.14 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 32.5 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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Solubility in Formulation 4: 2 mg/mL (8.09 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication (<60°C).

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 (Please use freshly prepared in vivo formulations for optimal results.)