CLINICAL PHARMACOLOGY
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-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/1.73m2.1
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 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 Given Once a Day for 7 Days | Flagyl ER 750 mg daily
Mean±SD (N=24) |
|---|
| Parameter | fed | fasted |
|---|
| AUC(0–24) (µg∙hr/mL) | 211±60.0 | 198±75.3 |
| Cmax (µg/mL) | 19.4±4.7 | 12.5±4.8 |
| Cmin (µg/mL) | 3.4±2.0 | 4.2±2.2 |
| Tmax (hrs) | 4.6±2.4 | 6.8±2.8 |
| T¤ (hrs) | 7.4±1.6 | 8.7±2.2 |
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:
| MIC (µg/mL) | Interpretation |
|---|
| ≤ 8 | Susceptible (S) |
| 16 | Intermediate (I) |
| ≥32 | Resistant (R) |
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:
| Microorganism | MIC (µg/mL) |
|---|
| Bacteroides fragilis ATCC 25285 | 0.25–1.0 |
| Bacteroides thetaiotaomicron ATCC 29741 | 0.5–2.0 |
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