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Pharmacology: Pharmacodynamics: Tablet: Metronidazole is an anti-infective agent belonging to the 5-nitroimidazole group. The antibacterial spectrum of metronidazole concerns exclusively anaerobic microorganisms.
Susceptible species: More than 90% of the species are susceptible: Peptostreptococcus, C. perfringens, C. difficile, Bacteroides fragilis, Bacteroides sp., Fusobacterium, Clostridium sp., Prevotella, Veillonella.
Species with inconstant susceptibility: The susceptibility of the pathogens should be tested by an antibiogram: Bifidobacterium, Eubacterium.
Normally resistant species: More than 50% of the species are resistant: Propionibacterium, Actinomyces, Mobilincus.
The antiparasitic activity concerns: Trichomonas vaginalis, Giardia intestinalis, Entamoeba histolytica.
Oral suspension: Specific bactericidal activity against important obligate anaerobes.
Pharmacokinetics: Tablet: Absorption: Metronidazole is rapidly absorbed following oral administration, at least 80% in less than one hour. The peak serum concentration achieved following oral administration is similar to those obtained following intravenous administration of equivalent doses.
The oral bioavailability is 100% and is not modified by simultaneous ingestion of food.
Distribution: Approximately one hour after a single dose administration of 500 mg of metronidazole, the peak serum concentration is, on average, 10 μg/mL.
The plasma half-life is between 8 to 10 hours.
The protein binding is low: <20%.
The volume of distribution is large, on average 40 L (i.e. 0.65 L/kg).
Diffusion of the drug is rapid and extensive with concentrations close to serum levels in the lungs, kidneys, liver, skin, bile, CSF, saliva, seminal fluid and vaginal secretions.
Metronidazole crosses the placental barrier and is excreted in breast milk.
Metabolism: Metronidazole is primarily metabolized in the liver. Oxidation yields two main metabolites: The alcoholic metabolite, the primary metabolite, with a bactericidal activity against anaerobic bacteria equal to approximately 30% of that of metronidazole, and with an elimination half-life of 11 hours.
The acid metabolite, in small amounts, and with a bactericidal activity approximately equal to 5% of that of metronidazole.
Elimination: High liver and biliary concentration. Low concentration in the colon.
Little fecal elimination.
Excretion is primarily urinary, shown by the fact that the metronidazole and its oxidation metabolites excreted in the urine account for approximately 35 to 65% of the administered dose.
Oral suspension: Metronidazole is readily and almost absorbed after oral doses. Peak plasma conc of about 6 and 12 micrograms/mL are achieved, usually within 1 to 2 hours, after single doses of 250 and 500 mg respectively. Some accumulation occurs and consequently there are higher conc when multiple doses are given. Absorption may be delayed, but is not reduced overall by food. Metronidazole benzoate given by mouth is hydrolysed in the gastrointestinal tract to release metronidazole, which in turn is then absorbed.
Metronidazole is widely distributed. It appears in most body tissues, and fluids including bile, bone, breast milk, cerebral abscesses, CSF, liver and liver abscess, saliva, seminal fluid, and vaginal secretions, and achieves concentrations similar to those in plasma. It also crosses the placenta rapidly and enters fetal circulation. Not more than 20% is bound to plasma proteins.
The elimination half-life of metronidazole is about 8 hr that of hydroxy metabolite is slightly longer. The half-life of metronidazole is reported to be longer in neonates and in patients with severe hepatic impairment, that of the hydroxy metabolite is prolonged in patients with substantial renal impairment.
Toxicology: Tablet: Non-Clinical Safety Data: Carcinogenicity: Metronidazole has been shown to be carcinogenic in the mouse and in the rat. However similar studies in the hamster have given negative results and epidemiological studies in humans have provided no evidence of an increased carcinogenic risk in humans.
Therefore, the use of metronidazole for prolonged treatment duration should be carefully weighed (see Warnings and Precautions under Precautions).
Mutagenicity: Metronidazole has been shown to be mutagenic in bacteria in vitro. In studies conducted in mammalian cells in vitro as well as in rodent or humans in vivo, there was inadequate evidence of a mutagenic effect of metronidazole, with some studies reporting mutagenic effects, while other studies were negative.
Therefore, the use of metronidazole for prolonged treatment duration should be carefully weighed (see Warnings and Precautions under Precautions).
