Single‐ and multiple‐dose metronidazole kinetics

Kinetics of metronidazole and its metabolites were examined after single oral and intravenous doses and multiple oral doses in seven subjects by a sensitive HPLC assay. After 400 mg metronidazole IV, mean Vd β was 1.05 l/kg. Mean plasma t½ was 8.3 hr with a Cl TBC of 1.31 ml/min/kg. Clearance to the major metabolites, 2‐hydroxy‐metronidazole and 1‐acetic acid metronidazole, accounted for over 90% of the Cl TBC . After a single oral 400‐mg metronidazole dose, the development of peak metronidazole plasma concentrations of 6.9 μg/ml averaged 2.3 hr after dosing. Systemic oral bioavailability was complete (98.9%). During twice‐daily multiple metronidazole dosing, 400 mg, metronidazole kinetics were the same. Elimination t½ was 8.3 hr and average predicted steady‐state metronidazole concentrations during one dosing interval (6.3 ± 0.5 μg/ml; mean ± SE) were equal to the observed concentrations (6.9 ± 1 μg/ml). Urinary excretion of unchanged metronidazole was below 10% of the total dose. Seventy‐five percent of the dose was 2‐hydroxy‐metronidazole and 1‐acetic acid metronidazole, and 15% was conjugates of metronidazole and 2‐hydroxy‐metronidazole. Clinical Pharmacology and Therapeutics (1983) 34, 481–487; doi: 10.1038/clpt.1983.201