A comparison of the pharmacokinetics of metronidazole in man after oral administration of single doses of benzoylmetronidazole and metronidazole.

Abstract

Three healthy male volunteers were treated with benzoylmetronidazole [an antibacterial and antiparasitic agent] suspension (3.2 g = 2 g metronidazole) in a pilot study to investigate the absorption of benzoylmetronidazole into the systemic circulation. Another 10 healthy male volunteers took part in a crossover study to compare the pharmacokinetics of metronidazole and its principal oxidative metabolites after administration of benzoylmetronidazole (equivalent to 2 g or 400 mg of metronidazole) or metronidazole (400 mg). The plasma pharmacokinetics of metronidazole and metabolite I [1-(2-hydroxyethyl)-2-methyl-5-nitroimidazole] and plasma and urinary concentrations of these, plus benzoylmetronidazole and metabolite II [2-methyl-5-nitroimidazole-1-acetic acid], were determined with specific and sensitive high performance liquid chromatographic assay procedures. No benzoylmetronidazole was observed in any plasma or urine sample assayed. The values for and times of the highest observed plasma metronidazole concentrations after a single oral dose of benzoylmetronidazole, equivalent to 2 g and 400 mg metronidazole, were 17 .mu.g/ml at 5.1 h after dosing and 4.6 .mu.g/ml at 3.2 h after dosing, respectively. Following oral administration of metronidazole (400 mg), the comparable values were 8.5 .mu.g/ml at 0.8 h after dosing. Peak plasma concentrations of metabolite I after each dose were comparable with each other when corrected for the amount of metronidazole reaching the systemic circulation. The peak concentrations of this metabolite were markedly lower than the peak metronidazole concentrations in the same volunteer. Metabolite II was observed in low concentrations (0.8 .mu.g/ml or less) in plasma at a few time intervals after administration of the higher dose of benzoylmetronidazole and was not detected at any time interval after administration of benzoylmetronidazole (640 mg, equivalent to 400 mg metronidazole) or metronidazole (400 mg). Pharmacokinetic parameters of metronidazole absorption are markedly different after administration of benzoylmetronidazole than after dosing with metronidazole, but the pharmacokinetic parameters of metronidazole and metabolite I elimination are essentially identical after equimolar doses of each form of the drug. The systemic availability of metronidazole derived from benzoylmetronidazole is .apprx. 80% of that from metronidazole and is dose independent over the range studied. The mean value for minimum plasma metronidazole concentration at steady state during the o.d. [once daily] administration of benzoylmetronidazole (3.2 g = 2 g metronidazole) was predicted (from these single-dose data) to be 6.2 .mu.g/ml. The majority of patients will apparently maintain therapeutic plasma metronidazole concentrations for the whole of the dosing interval during a o.d. dosing regimen. This oral liquid formulation of metronidazole may be a suitable alternative to other presentations of the drug.