Pharmacokinetics of metronidazole and its metabolites in reduced renal function

Abstract

The pharmacokinetics of metronidazole (M), hydroxymetronidazole (OH-M), and acetylhydroxymetronidazole (A-M) were determined after a single intravenous dose of 0.5 g metronidazole. This was administered as an intravenous infusion during 30 min to 10 healthy volunteers and 24 patients with varying degrees of reduced renal function. Serum and urine concentrations were assayed by high-pressure liquid chromatography. The peak concentrations of the hydroxymetabolite appeared within an hour in the healthy volunteers and after a mean of 2.6 h (range 0.5-12.5 h) in the patients with reduced renal function. Analogously, the peak of the acetylmetabolite appeared later, at an average of 6.9 h and a range of 0.5-36.5 h. A-M was not observed in serum of the healthy subjects nor in 6 of the patients, but was recovered in urine of all subjects. The serum concentrations of M and OH-M were detectable throughout the 48 h monitored. Total urinary recovery in healthy subjects was 108.0% of the dose. This breaks down to 18.4% metronidazole, 62.4% OH-M, and 27.2% A-M. In the patients with reduced renal function, the relative contribution of A-M is higher than that of the other two products. The serum half-life of metronidazole was 7.1 in the healthy subjects and similar in reduced renal function (range 3.5-12.4 h). The serum half-life of OH-M was 18.0 h in the healthy and ranged 9.6-85.5 h in renal impairment. Long half-life values of 8.5-36.5 h were observed for A-M. Accumulation of OH-M and particularly of A-M was marked in reduced renal function. In the normal healthy volunteers, the coefficient of the steady-state distribution volume averaged 0.404 liter/kg of the terminal phase distribution volume 0.542 liter/kg, and the total body clearance 3.1 liter/h. The total body clearance of the unchanged compound was not influenced by reduced renal function.