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 μg/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 dose-concentration 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 μg/ml and minimum concentrations 15 μg/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 μg/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 1-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 β (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. The pharmacokinetics of metronidazole do not appear to differ significantly in neonates, patients seriously ill with anaerobic infections, or during pregnancy. However, dose modification is necessary in neonates because of the slower elimination of the drug. In patients with renal failure, although the serum half-life of metronidazole does not change, the half-life of the hydroxy metabolite increases 4-fold and accumulates in the serum. Haemodialysis effectively removes metronidazole and, to a lesser extent, the hydroxy metabolite, reducing the half-life of the former to 2.6 hours and the latter to 7.8 hours, and diarrhoea, a reversible leucocytopenia, and various neurological toxicities (the latter generally associated with large doses over a prolonged period). Potentially serious toxicities including tumourigenicity, dysmorphogenicity, and mutagenicity inferred from certain animal models and bacterial test systems have not been confirmed in humans. The pharmacokinetic properties of metronidazole complement its excellent microbiological activity against anaerobic organisms, making it a very effective drug in the treatment of anaerobic infections.