Pharmacokinetics of Metronidazole as Determined by Bioassay

Abstract

The pharmacokinetics of metronidazole, a drug effective in vitro against most anaerobic bacteria and promising in treating anaerobic infections, are described. Serum and urine levels after single and multiple doses in 10 adult male volunteers were measured by an agar well diffusion bioassay using clostridial species as the test organisms under anaerobic conditions. Peak serum levels averaged 11.5 ,ug/ml and 6.2 ug/ml after single 500-mg and 250-mg doses, respectively. Renal clearance was only 10.2 ml/min per 1.73 M2, and less than 20% of the administered dose was recovered in the urine as active drug in 24 h. The average serum half-life was 8.7 h, and there was no protein binding as determined by an ultrafiltration method. With multiple doses of metronidazole (500 mg four times a day and 250 mg three times a day), blood levels increased progressively for the first few doses and then leveled off, with no significant accumulation occurring between 3 and 7 days. On 250 mg three times a day, serum levels just before the 8 a.m. dose (12 h after the preceding dose) on the third day averaged 3.9 Mg/ml, and before the 8 p.m. dose, 5.7 Mg/ml. For the higher, 500-mg dose (four times a day) regimen, the corresponding minimum serum levels were 13.1 Mig/ml at 8 a.m. and 21.3 Mg/ml at 8 p.m. Peak levels would have been about 10 ,g/ml higher, and since the minimum inhibitory concentrations of most anaerobes including Bacteroides fragilis are less than 6 Mg/ ml, these concentrations should be highly effective therapeutically, even for severe infections.With the increasing awareness of the pathogenicity of anaerobic bacteria, antimicrobial agents which were effective against these organisms are receiving greater attention. Metronidazole [1-(,-hydroxyethyl)-2-methyl-5-nitroimidazole], which has been used effectively for many years against certain protozoal infec-

Liquid chromatographic assay for metronidazole and tinidazole: pharmacokinetic and metabolic studies in human subjects

“…The half-lives determined with bioassays (10,14,17) were higher, presumably due to the biological activity of the hydroxy metabolite (18). The serum levels of this metabolite described above agree well with earlier observations (7,8).…”

Pharmacokinetics of Metronidazole in Pregnant Women

“…These results are in good agreement with the studies of Taylor et al [33], who used a centrifuge-type ultrafiltra tion method. Other investigators found a lower protein binding [22,24], It is unlikely that at therapeutic concentrations the bind ing of metronidazole to plasma albumin ex erts an appreciable influence on pharma cokinetics and thus pharmacodynamics, since the association constant is less than 104M-1. This property and the small size of the metronidazole molecule favors a rap id diffusion to all tissues and fluid compart ments [3.…”

“…This is in ac cordance with results of other authors [14,31], who estimated metronidazole with chemical methods in the urine of nonpreg nant women. Using the bioassay, the ob served urine concentrations and recovery were lower [22]. Chemical methods deter mined the unchanged drug in urine as well as a significant quantity of biologically inac tive metabolites [22,31,33], In all our cases the urinary concentrations were chemotherapeutically effective.…”

Metronidazole Bioassay

“…The metabolism of metronidazole and the basis of its activity are still poorly understood. Recently a bioassay utilizing Clostridium was described as being useful for determining the concentration of metronidazole in body fluids (7). The purpose of this report is to present findings which suggest that this bioassay may be restricted in its usefulness.…”