Pharmacokinetics

Disposition of metronidazole in the body is similar for both oral and intravenous dosage forms, with an average elimination half-life in healthy humans of 8 hours.

The major route of elimination of metronidazole and its metabolites is via the urine (60% to 80% of the dose), with fecal excretion accounting for 6% to 15% of the dose. The metabolites that appear in the urine result primarily from side-chain oxidation [1(βhydroxyethyl)-2-hydroxymethyl-5-nitroimidazole and 2-methyl-5-nitroimidazole-1-ylacetic acid] and glucuronide conjugation, with unchanged metronidazole accounting for approximately 20% of the total. Renal clearance of metronidazole is approximately 10 mL/ min/1.73m^2.1

Flagyl ER 750 mg tablets contain 750 mg of metronidazole in an extended release formulation which allows for once-daily dosing. The steady state pharmacokinetics were determined in 24 healthy adult female subjects with a mean ± SD age of 28.8 ± 8.8 years (range: 19–46).² The pharmacokinetic parameters of metronidazole after administration of Flagyl ER (metronidazole extended release tablets) 750 mg under fed and fasting conditions are summarized in the following table.

Steady State Pharmacokinetic Parameters of Metronidazole after 750 mg of Flagyl ER (metronidazole extended release tablets) Given Once a Day for 7 Days

Relative to the fasting state, the rate of metronidazole absorption from the extended release tablet is increased in the fed state resulting in alteration of the extended release characteristics.

Decreased renal function does not alter the single-dose pharmacokinetics of metronidazole. However, plasma clearance of metronidazole is decreased in patients with decreased liver function.

Microbiology

Metronidazole exerts an antimicrobial effect in an anaerobic environment by the following possible mechanism: Once metronidazole enters the organism, the drug is reduced by intra-cellular electron transport proteins. Because of this alteration to the metronidazole molecule, a concentration gradient is maintained which promotes the drug's intracellular transport. Presumably, free radicals are formed which, in turn, react with cellular components resulting in death of the microorganism.

The following in vitro data are available, but their clinical significance is unknown:

Metronidazole exhibits in vitro minimal inhibitory concentrations (MIC's) of 8 μg/mL or less against most ( ≥ 90%) strains of the following microorganisms; however, the safety and effectiveness of metronidazole in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled clinical trials.

Gram-positive anaerobes

Clostridium species
Eubacterium species
Peptococcus niger
Peptostreptococcus species

Gram-negative anaerobes

Bacteroides fragilis group (B. fragilis, B. distasonis, B. ovatus, B. thetaiotaomicron, B. vulgatus)
Fusobacterium species
Prevotella species (P. bivia, P. buccae, P. disiens)
Porphyromonas species

Protozoal parasites

Entamoeba histolytica
Trichomonas vaginalis

Metronidazole has shown minimal to no activity against clinically relevant facultative anaerobes or obligate aerobes. Metronidazole has minimal activity against Lactobacillus spp and other aerobic microorganisms commonly isolated from the vaginal tract.

Susceptibility Tests

Dilution techniques

Quantitative methods that are used to determine minimum inhibitory concentrations provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. For anaerobic bacteria, the susceptibility to metronidazole can be determined by the reference agar dilution method or by alternate standardized test methods.³ The MIC values obtained should be interpreted according to the following criteria:

For protozoal parasites: Standardized tests do not exist for use in clinical microbiology laboratories.

A report of “Susceptible” indicates that the pathogen is likely to be inhibited by usually achievable concentrations of the antimicrobial compound in the blood. A report of “Intermediate” indicates that the result should be considered equivocal, and if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where high dosage of drug can be used. This category also provides a buffer zone which prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of “Resistant” indicates that usually achievable concentrations of the antimicrobial compound in the blood are unlikely to be inhibitory and other therapy should be selected.

Standardized susceptibility test procedures require the use of laboratory control microorganisms that are used to control the technical aspects of the laboratory procedures. Standard metronidazole powder should provide the following MIC values:

Clinical Studies

BV is a clinical syndrome that results from a replacement of the normal, Lactobacillus-dominant flora with several other organisms including Gardnerella vaginalis, Mobiluncus spp, Mycoplasma hominis and anaerobes (Peptostreptococcus spp and Bacteroides spp).

Flagyl ER (metronidazole extended release tablets) was studied in patients with BV in two randomized, multicenter, well-controlled, investigator blind clinical trials.4,5 A total of 557 otherwise healthy nonpregnant patients with BV were randomized to treatment with Flagyl ER (metronidazole extended release tablets) once a day for 7 days (n=270) or 2% clindamycin vaginal cream one applicator full (5 grams) once a day for 7 days (n=287).

The primary efficacy endpoint for each treatment regimen was defined as clinical cure assessed at 28–32 days post-therapy. Clinical cure was defined as a return to normal of the vaginal pH ( ≤ 4.5), absence of a “fishy” amine odor, and absence of clue cells.

The study results are presented in the table below:

Clinical Cure Rates at One Month

At one month post-therapy the pH of the vagina returned to normal earlier and in a greater percentage of patients in the Flagyl ER (metronidazole extended release tablets) treatment group when compared to the 2% clindamycin vaginal cream group; 72% vs 65%, respectively. Likewise, Flagyl ER (metronidazole extended release tablets) restored the normal Lactobacillus-predominant vaginal flora in a larger percentage of patients at one month post-therapy when compared to the 2% clindamycin treated group; 74% vs 63%, respectively.

REFERENCES

1. Salas-Herrera IG, Pearson RM, Johnston A, and Turner P. Concentration of metronidazole in cervical mucus and serum after single and repeated oral doses. J Antimicrobial Chemotherapy 1991; 28:283–289.

2. Metronidazole modified-release tablet multiple-dose bioequivalency study (fed/fasting). G.D. Searle & Co., Protocol No. S13-94-02-014; Report No. S13-95-06-014, 11 July 1995.

3. National Committee for Clinical Laboratory Standards, Methods for Antimicrobial Susceptibility Testing of Anaerobic Bacteria—Third Edition. Approved Standard NCCLS Document M11-A3, Vol. 13, No. 26, NCCLS, Villanova, PA, December, 1993.

Last reviewed on RxList: 9/15/2010
This monograph has been modified to include the generic and brand name in many instances.