Clinical Pharmacokinetics of Metronidazole

Abstract

The clinical pharmacokinetics of metronidazole following oral, intravenous, rectal, and intravaginal doses are described. Peak serum concentrations are quite similar after oral or intravenous administration and average approximately 10 pg/ml after a single 500mg dose. After an oral dose the peak serum concentration is reached approximately 1 hour after administration. Food does not significantly affect absorption, and the bioavailability of the dose approaches 100%. For both intravenous and oral administration, a linear doseconcentration curve pertained for usual therapeutic doses between 200 and 2000mg.Multiple oral or intravenous doses given every 6 to 8 hours result in some drug accumulation with higher serum concentrations as compared with single doses. On an intravenous dose regimen of 500mg every 8 hours, maximum metronidazole serum concentrations average 25 p.glml and minimum concentrations 15 p.g/ml. Rectal administration of metronidazole by suppository resulted in peak serum concentrations approximately one-half those following equivalent oral doses and occurred at 4 hours after administration; the bioavailability of the rectal suppository was approximately 80%. From the limited data available, the systemic absorption of intravaginal metronidazole is very slow with peak serum concentrations of approximately 2 p.g/ml being attained 8 to 24 hours after administration of a 500mg dose.Metronidazole is excreted in the urine as unchanged drug and primarily oxidative metabolites, the major compounds being the hydroxy and acid metabolites. The degree of urinary excretion is dependent upon the assay used. By bioassay, 15 to 20% of the administered dose is excreted as bioactive drug. By high pressure liquid chromatography, in which unchanged metronidazole and the hydroxy and acid metabolites are measured separately, total excretion of these compounds after 48 hours is approximately 30%, with the hydroxy metabolite being the primary excretory product. Detailed pharmacokinetic analysiS of metronidazole has been performed using I-compartment and 2-compartment open models. The serum half-life of unchanged metronidazole averaged 8.2 hours, as determined by specific chemical methods, whereas using bioassay methods the half-life was somewhat longer. A 2-compartment open model analysis described the serum concentration-time curve with a rapid a (distribution) phase (half-life 1.24 hours)and a slower /3 (elimination) phase (half-life 9.76 hours). Metronidazole has a large apparent volume of distribution and serum protein binding of 20% or less. In multiple-dose regimens the hydroxy metabolite of metronidazole may be present in concentrations up to 30% of those of the parent drug with a half-life of 9. 7 hours. The acid metabolite is rarely detected in serum. Metronidazole is widely distributed throughout the body with tissue levels, in most cases, approximating serum levels. This is especially important in the central nervous system where the drug readily crosses both the blood-brain and blood-cerebrospinal flUid barriers....

Pharmacokinetics of ornidazole in patients with renal insufficiency; influence of haemodialysis and peritoneal dialysis.

“…Low molecular weight, solubility, lack of protein binding and small volume of distribution are physicochemical and pharmacokinetic characteristics which favour elimination by haemodialysis (Gibson & Nelson, 1977;Maher, 1977;Nolph et al, 1978;Watanabe, 1977). Similar results have been reported for metronidazole (Ralph, 1983 (Schwartz et al, 1979) and they can be measured with the h.p.l.c. method used.…”

Pharmacokinetics and tissue penetration of a single dose of ornidazole (1,000 milligrams intravenously) for antibiotic prophylaxis in colorectal surgery

“…Since Bacteroides fragilis and other anaerobic bacteria are among the main pathogens encountered in infections after colorectal surgery, antibiotics with a spectrum of activity extended to these organisms are usually advocated (1). Antibiotic regimens which do not eliminate anaerobic fecal pathogens fail to control postoperative septic complications of colorectal operations (5, 13).Nitroimidazole derivatives such as metronidazole are commonly used in this situation (3,8,12,22 …”

Pharmacokinetics and tissue penetration of a single 1,000-milligram, intravenous dose of metronidazole for antibiotic prophylaxis of colorectal surgery

“…The elimination half-life and the volume of distribution was slightly higher than values observed in normal subjects. No major change in total body clearance was observed (21). In view of these results, the single dose used in this study (1,000 mg given i.v.)…”