DNA synthesis

Metronidazole (135 mg/kg/d; p.o.; 28 d) can penetrate the blood-brain barrier and, when given to rats over an extended period of time, show neurotoxicity[3].
Metronidazole (1 g/L; p.o.; 4 weeks) causes atrophy in skeletal muscle and alters the expression of genes related to metabolic regulation and the peripheral circadian rhythm machinery of the muscle[4].

Cell Line: Blastocystis sp. Cells
Concentration: 0.1 μg/mL-0.01 mg/mL
Incubation Time: 12, 24, 48, 60, 72, 84, 96 hours
Result: Decreased cell diameter, as a hallmark of an apoptotic cell, and resulted cell shrinkage.

Sprague-Dawley (SD) rats (200-220 g)
135 mg/kg
Oral gavage; once daily; 28 days

Absorption, Distribution and Excretion
After the intravenous infusion of a 1.5g dose, peak concentration was reached within 1 hour and was peak level of 30-40 mg/L. When a multiple-dose regimen of 500mg three times a day administered intravenously, steady-state concentrations were achieved within about 3 days and peak concentration was measured at 26 mg/L. When administered orally in the tablet form, metronidazole is absorbed entirely absorbed, showing a bioavailability of greater than 90%. One resource indicates that Cmax after a single oral dose of 500mg metronidazole ranges from 8 to 13 mg/L, with a Tmax of 25 minutes to 4 hours. The AUC following a single 500mg oral dose of metronidazole was 122 ± 10.3 mg/L • h. A note on the absorption of topical preparations Insignificant percutaneous absorption of metronidazole occurs after the application of 1% metronidazole cream topically. Healthy volunteers applied one 100 mg dose of 14C-labelled metronidazole 2% cream to unbroken skin. After 12 hours, metronidazole was not detected in the plasma. Approximately 0.1% to 1% of the administered metronidazole was measured in the urine and feces.
Metronidazole and metabolites are 60 to 80% eliminated in the urine, and 6-15% excreted in the feces.
Metronidazole is widely distributed throughout the body and various body fluids. They include the bile, saliva, breastmilk, cerebrospinal fluid, and the placenta. Steady-state volume distribution of metronidazole in adults ranges from 0.51 to 1.1 L/kg. It attains 60 to 100% of plasma concentrations in various tissues, such as the central nervous system, however, is not measured in high concentrations in the placental tissue.
Dose adjustments may be required in patients with hepatic impairment, as clearance is impaired in these patients. The clearance of metronidazole in the kidneys is estimated at 10 mL/min/1.73 m2. The total clearance from serum is about 2.1 to 6.4 L/h/kg.
Well absorbed orally; bioavailability at least 80%.
Distributed to saliva, bile, seminal fluid, breast milk, bone, liver and liver abscesses, lungs, and vaginal secretions; crosses the placenta and blood-brain barrier, also.
At least 80% of an oral dose of metronidazole is absorbed from the GI tract. Following oral administration of a single 250-mg, 500-mg, or 2-g dose of metronidazole as immediate-release (conventional) preparations in healthy, fasting adults, peak plasma concentrations of unchanged drug and active metabolites are attained within 1-3 hours and average 4.6-6.5 ug/mL, 11.5-13 ug/mL, and 30-45 ug/mL, respectively. When a single 750-mg dose of metronidazole is administered as two 375-mg capsules or three 250-mg conventional tablets in healthy, fasting adult women, average peak plasma concentrations of unchanged drug and active metabolites of 20.4-21.4 ug/mL are attained in an average of 1.4-1.6 hours; metronidazole capsules and conventional tablets are bioequivalent at a single dose of 750 mg. The rate of absorption and peak plasma concentrations of metronidazole are decreased when conventional tablets or capsules of the drug are administered with food; however, the total amount of drug absorbed is not affected.
Following oral administration of metronidazole 750 mg once daily as the extended-release tablet for 7 consecutive days in healthy, adult women, steady-state peak plasma concentrations average 12.5 mcg/mL and are attained an average of 6.8 hours after the dose when the drug is given under fasting conditions; when the drug is given at the same dosage under nonfasting conditions, steady-state peak plasma concentrations average 19.4 mcg/mL and are attained an average of 4.6 hours after the dose. Administration of metronidazole extended-release tablets with food increases the rate of absorption and peak plasma concentrations of the drug. According to the manufacturer, metronidazole extended-release and conventional tablets are bioequivalent at a dose of 750 mg given under fasting conditions.
For more Absorption, Distribution and Excretion (Complete) data for METRONIDAZOLE (12 total), please visit the HSDB record page.

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Metabolism / Metabolites
Metronidazole undergoes hepatic metabolism via hydroxylation, oxidation, and glucuronidation. The metabolism of metronidazole yields 5 metabolites. The hydroxy metabolite, 1-(2-hydroxy-ethyl)-2-hydroxy methyl-5-nitroimidazole, is considered the major active metabolite. Unchanged metronidazole is found in the plasma along with small amounts of its 2- hydroxymethyl metabolite. Several metabolites of metronidazole are found in the urine. They are primarily a product of side-chain oxidation in addition to glucuronide conjugation. Only 20% of the dose found in the urine is accounted for by unchanged metronidazole. The two main oxidative metabolites of metronidazole are hydroxy and acetic acid metabolites.
Approximately 30-60% of an oral or IV dose of metronidazole is metabolized in the liver by hydroxylation, side-chain oxidation, and glucuronide conjugation. The major metabolite, 2-hydroxy metronidazole, has some antibacterial and antiprotozoal activity.
... Four other nitro-group-containing metabolites have been identified, each derived from side-chain oxidation of ethyl and/or methyl group. They include 1-acetic acid-2-methyl-5-nitroimidazole and 1-(2-hydroxyethyl)-2-carboxylic acid-5-nitroimidazole salt.
The liver is the main site of metabolism, and this accounts for over 50% of the systemic clearance of metronidazole. The 2 principal metabolites result from oxidation of side chains, a hydroxy derivative and an acid. The hydroxy metabolite has a longer half-life (about 12 hr) and nearly 50% of the antitrichomonal activity of metronidazole. Formation of glucuronides also is observed. Small quantities of reduced metabolites, including ring-cleavage products, are formed by the gut flora. The urine of some patients may be reddish-brown owing to the presence of unidentified pigments derived from the drug.
Hepatic metabolism by hydroxylation, oxidation, and glucuronidation.
Half Life: 6-8 hours

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Biological Half-Life
The elimination half-life of metronidazole is 7.3 ± 1.0 after a single 500mg IV dose in healthy subjects. Another resource indicates that the elimination half-life for metronidazole ranges from 6 to 10 hours.
The plasma half-life of metronidazole is reported to be 6-8 hours in adults with normal renal and hepatic function. In one study using radiolabeled metronidazole hydrochloride, the half-life of unchanged metronidazole averaged 7.7 hours and the half-life of total radioactivity averaged 11.9 hours. The plasma half-life of metronidazole is not affected by changes in renal function; however, the half-life may be prolonged in patients with impaired hepatic function. In one study in adults with alcoholic liver disease and impaired hepatic function, half-life of metronidazole averaged 18.3 hours (range: 10.3-29.5 hours).
Half-life: Neonates 25-75 hours; Others: 6-8 hours, increases with hepatic impairment.
The elimination half-life in dogs is 4.5hr, and in horses 1.5-3.3hr

Toxicity Summary
Metronidazole is a prodrug. Unionized metronidazole is selective for anaerobic bacteria due to their ability to intracellularly reduce metronidazole to its active form. This reduced metronidazole then covalently binds to DNA, disrupt its helical structure, inhibiting bacterial nucleic acid synthesis and resulting in bacterial cell death.

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Toxicity Data
LD50=500 mg/kg/day (orally in rat).

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Interactions
It is recommended that metronidazole not be used concurrently with, or for at least 1 day following, ingestion of alcohol; accumulation of acetaldehyde by interference with the oxidation of alcohol may occur, resulting in disulfiram-like effects such as abdominal cramps, nausea, vomiting, headache, or flushing; in addition, modifications in the taste of alcoholic beverages have been reported during concurrent use.
Effects may be potentiated when /coumarin- or indandione-derivative anticoagulants/ are used concurrently with metronidazole, because of inhibition of enzymatic metabolism of anticoagulants; periodic prothrombin time determinations may be required during therapy to determine if dosage adjustments of anticoagulants are necessary.
Hepatic metabolism of metronidazole may be decreased when metronidazole and cimetidine are used concurrently, possibly resulting in delayed elimination and increased serum metronidazole concentrations; monitoring of serum concentrations as a guide to dosage is recommended since dosage adjustments of metronidazole may be necessary during and after cimetidine therapy.
It is recommended that metronidazole not be used concurrently with, or for 2 weeks following, disulfiram in alcoholic patients; such use may result in confusion and psychotic reactions because of combined toxicity.
For more Interactions (Complete) data for METRONIDAZOLE (12 total), please visit the HSDB record page.

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Non-Human Toxicity Values
LD50 Albino Rat oral > 5 g/kg

[1]. Antimicrob Agents Chemother . 1999 Jul;43(7):1533-41.

[2]. Drugs . 1991 Sep;42(3):428-67.

[3]. J Bacteriol . 2000 Sep;182(18):5091-6.

Therapeutic Uses
Mesh Heading: Anti-infective agents, antiprotozoal agents, radiation-sensitizing agents
MEDICATION (VET): Antiprotozoal (Trichomonas); antiamebic; antibacterial
MEDICATION (VET): The success of metronidazole in treating human infections of giardiasis, vaginal and oral trichomoniasis, and hepatic and intestinal amoebiasis has lead to investigation of its potential use against certain protozoan diseases of domestic animals. These are principally bovine urogenital trichomoniasis and canine, feline, or primate intestinal giardiasis, trichomoniasis, amoebiasis, or Balantidium infection. ...
Oral metronidazole (extended release formulation) is used in the treatment of bacterial vaginosis caused by Gardnerella vaginalis, Mobiluncus spp, mycoplasma hominis and anaerobes (peptostreptococcus spp and Bacteroides spp). /Included in US or Canadian product labeling/
For more Therapeutic Uses (Complete) data for METRONIDAZOLE (25 total), please visit the HSDB record page.

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Drug Warnings
Metronidazole crosses the placenta and enters the fetal circulation rapidly. Adequate and well-controlled studies in humans have not been done. ... However, the use of metronidazole in the treatment of trichomoniasis is not recommended during the first trimester. If metronidazole is used during the second and the third trimesters for trichomoniasis it is recommended that its use be limited to those patients whose symptoms are not controlled by local palliative treatment. Also, the 1 day course of therapy should not be used since this results in higher maternal and fetal serum concentrations.
No information is available on the relationship of age to the effects of metronidazole in geriatric patients. However, elderly patients are more likely to have an age-related decrease in hepatic function, which may require an adjustment in dosage in patients receiving metronidazole.
Peripheral neuropathy, characterized by numbness, tingling, or paresthesia of an extremity, and convulsive seizures have been reported rarely with oral or IV metronidazole. Peripheral neuropathy is usually reversible if metronidazole is discontinued but may persist in patients who receive prolonged therapy or higher than recommended dosage of the drug. Dizziness, vertigo, incoordination, ataxia, confusion, irritability, depression, weakness, insomnia, headache, syncope, tinnitus, and hearing loss have also occurred with metronidazole. Headache occurred in 18% of nonpregnant women receiving oral metronidazole (administered as extended-release tablets) for bacterial vaginosis, and among those reporting headache, 10% described it as severe.
Urethral burning or discomfort, dysuria, cystitis, polyuria, incontinence, a sense of pelvic pressure, dryness of the vagina or vulva, dyspareunia, and decreased libido have been reported with oral metronidazole. Urine may be dark or reddish-brown in color following oral or IV administration of metronidazole due to the presence of water-soluble pigments which result from metabolism of the drug. Vulvovaginal candidiasis (or yeast vaginitis) was reported in 15% of nonpregnant women receiving oral metronidazole (administered as extended-release tablets) and in 12% of those receiving clindamycin phosphate (2% clindamycin) vaginal cream in a comparative study for the treatment of bacterial vaginosis. Although a definite causal relationship to the drug has not been established, genital pruritus, dysmenorrhea, and urinary tract infection have been reported in 5, 3, and 2%, respectively, of nonpregnant women receiving oral metronidazole (administered as extended-release tablets) for the treatment of bacterial vaginosis.
For more Drug Warnings (Complete) data for METRONIDAZOLE (18 total), please visit the HSDB record page.

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Pharmacodynamics
Metronidazole treats amebiasis, trichomoniasis, and giardiasis, exerting both antibacterial and antiprotozoal activities. Metronidazole is an effective treatment for some anaerobic bacterial infections. Metronidazole has shown antibacterial activity against the majority of obligate anaerobes, however, during in vitro studies, it does not demonstrate significant action against facultative anaerobes or obligate aerobes. The nitro group reduction of metronidazole by anaerobic organisms is likely responsible for the drug's antimicrobial cytotoxic effects, causing DNA strand damage to microbes. A note on convulsions and neuropathy and carcinogenesis It is important to be aware of the risk of peripheral neuropathy and convulsions associated with metronidazole, especially at higher doses. If convulsions or numbness of an extremity occur, discontinue the drug immediately. Metronidazole has been found to be carcinogenic in mice and rats. The relevance to this effect in humans is unknown. It is advisable to only administer metronidazole when clinically necessary and only for its approved indications.

C6H9N3O3

171.15

171.064

C, 42.10; H, 5.30; N, 24.55; O, 28.04

443-48-1

1460293-84-8 (sodium); 13182-82-6 (acetate); 443-48-1 (free); 13182-89-3 (benzoate); 69198-10-3 (HCl); 443-48-1

4173

White to light yellow crystalline powder

1.5±0.1 g/cm3

405.4±25.0 °C at 760 mmHg

159-161 °C(lit.)

199.0±23.2 °C

0.0±1.0 mmHg at 25°C

1.612

-0.01

1

4

2

12

170

0

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

VAOCPAMSLUNLGC-UHFFFAOYSA-N

InChI=1S/C6H9N3O3/c1-5-7-4-6(9(11)12)8(5)2-3-10/h4,10H,2-3H2,1H3

2-(2-methyl-5-nitroimidazol-1-yl)ethanol

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: This product requires protection from light (avoid light exposure) during transportation and storage.

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

Solubility in Formulation 1: ≥ 2.08 mg/mL (12.15 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 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL 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: ≥ 2.08 mg/mL (12.15 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 20.8 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: ≥ 2.08 mg/mL (12.15 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 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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Solubility in Formulation 4: 12.5 mg/mL (73.04 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.)