Pharmacotherapeutic Group: Antimicrobial - antiprotozoal. ATC Code: J01K.
Pharmacology: Pharmacodynamics: Mechanism of Action: The mechanism of action of metronidazole is thought to involve reduction by bacterial nitroreductase to an unstable intermediate, which interact with DNA and effectively preventing further replication.
Pharmacokinetics: Absorption: Plasma concentration of metronidazole are proportional to the administered dose. An 8-hour intravenous infusion of 100 to 400 mg of metronidazole in healthy subjects showed a linear relationship between dose and peak plasma concentration.
Distribution: Metronidazole is widely distributed after absorption. It appears in most body tissues and fluids including bile, bone, breast milk, cerebral abscesses, CSF, liver and liver abscesses, saliva, seminal fluid, and vaginal secretions. It is less than 20% bound to plasma proteins in humans.
Metabolism: Metronidazole is metabolized in the liver by side-chain oxidation and glucuronide formation. The principal oxidative metabolites are the hydroxy metabolite which has an antibacterial activity and is detected in plasma and urine, and the acid metabolite which has virtually no antibacterial activity and is often not detected in plasma, but is excreted in urine.
Excretion: The elimination half-life of metronidazole is about 8 hours. The major route of elimination of metronidazole and its metabolites is via urine (60-80% of the dose), with fecal excretion accounting for 6-15% of the dose. The metabolites that appear in the urine result primarily from side-chain oxidation [1-(β-hydroxyethyl)-2-hydroxymethyl-5-nitromidazole and 2-methyl-5-nitroimidazole-1-yl-acetic acid] and glucuronide conjugation, with unchanged metronidazole accounting for approximately 20% of the total. Renal clearance of metronidazole is approximately 10 mL/min/1.73 m2.
Toxicology: Preclinical Safety Data: Metronidazole has shown evidence of carcinogenic activity in studies involving chronic, oral administration in mice and rats, but similar studies in the hamster gave negative results. Also, metronidazole has shown mutagenic activity in a number of in vitro assay system, but studies in mammals (in vivo) failed to demonstrate a potential for genetic damage.
Reproduction studies have been performed in pregnant mice at doses up to 1.5 times the human dose and have revealed no evidence of fetotoxicity due to metronidazole. Metronidazole administered intraperitoneally to pregnant mice at approximately the human dose caused fetotoxicity.
Microbiology: Metonidazole has been shown to have in vitro and clinical activity against the following organisms: Anaerobic gram-negative bacilli, including Bacteroides species, including Bacteroides fragilis group (B. ovatus, B. thetaiotaomicon, B. vulgatus) and Fusobacterium species.
Anaerobic gram-positive cocci, including Clostridium species and susceptible strains of Eubacterium, Peptococcus and Peptostreptococcus.