Pharmacokinetics of metronidazole in patients with varying degrees of renal failure.

Abstract

1 Twenty-nine patients with varying degrees of renal insufficiency were given a single intravenous dose of metronidazole (500 mg). Plasma and urinary concentrations of metronidazole and two major metabolites were determined using a specific high performance liquid chromatographic assay. 2 The pharmacokinetic parameters of metronidazole elimination half-life, area under the metronidazole concentration against time curve, apparent volume of distribution, metronidazole clearance and predicted degree of accumulation of metronidazole on repeated dosing were not statistically significantly affected by renal inadequacy of any degree. 3 The urinary excretion of metronidazole in patients with moderate or severe renal insufficiency was approximately half the value in healthy volunteers. The renal clearance of metronidazole was significantly greater in healthy volunteers compared to renally insufficient patients, but accounted for less than 10% of the total metronidazole clearance in all groups. 4 The elimination half-life and predicted accumulation (on three times daily dosing) of metabolite I [1-(2-hydroxyethyl)-2-hydroxymethyl-5-nitroimidazole] were significantly increased with decreasing renal function from 9.2 h and 2.3, respectively, in healthy volunteers to 34 h and 6.7, respectively, in patients with total renal failure. The degree of accumulation of this metabolite on repeated dosing is probably of limited clinical significance in all patients except those with severe or total renal failure for reasons detailed in the text. 5 The elimination half-life and predicted accumulation on three times daily dosing of metabolite II, [2-methyl-5-nitroimidazole-l-acetic acid] increased rapidly with decreasing renal function. The average steady-state concentrations predicted for a dosing regimen of metronidazole (500 mg) every 8 h were 0.83 ,ug/ml and 17 ,ug/ml in patients with moderate and severe renal insufficiency, respectively. 6 In patients with creatinine clearances greater than 10 ml/min, the accumulation of metronidazole or its two major oxidative metabolites is unlikely to have any toxicological implications. Patients with creatinine clearances of less than 10 ml/min and not receiving dialysis will show marked accumulation of both metabolites on repeated dosing. Removal of these metabolites is achieved during haemodialysis.

Novel Mechanistic PBPK Model to Predict Renal Clearance in Varying Stages of CKD by Incorporating Tubular Adaptation and Dynamic Passive Reabsorption

“…Indeed, this hypothesis is supported by observed data for various permeable drugs, such as pefloxacin, metronidazole, and minocycline. [11][12][13] For these drugs, the observed CL r in patients with CKD was reduced to 30-37% of healthy when residual GFR was only 4-9% of healthy, [11][12][13] demonstrating an over 7-fold disproportionality between the change in CL r and GFR.…”

“…CL r can also decrease less than proportionally with GFR in CKD stages 4 and 5 for highly renally reabsorbed drugs due to tubular adaptation/compensation processes. [11][12][13] Nonetheless, the most commonly accepted approach to predict CL r in patients with CKD is to follow the Intact Nephron Hypothesis 14 and assume all renal drug handling pathways and CL r decrease proportionally with filtration. Although this assumption is supported by clinical data for predominantly filtered drugs without significant secretion or reabsorption, 15,16 such proportional GFR scaling approach is inadequate to capture active secretion or passive reabsorption in severe CKD due to the complex disease effects on renal drug handling.…”

Clinical Pharmacokinetics of Antibiotics in Patients with Impaired Renal Function

“…Less than 20% of a dose is excreted unchanged in the urine and the t'/2 of the drug is unchanged in renal failure (Bergan & Thorsteinsson 1986;Houghton et al 1985;Kreeft et al 1983). The hydroxy metabolite has approximately 40% of metronidazole bioactivity, while the acetic acid metabolite is inactive (Turgeon et al 1983).…”

“…The hydroxy metabolite has approximately 40% of metronidazole bioactivity, while the acetic acid metabolite is inactive (Turgeon et al 1983). Both metabolites accumulate in renal failure, with the acetic acid metabolite accumulating to a greater degree (Bergan & Thorsteinsson 1986;Houghton et al 1985). This inactive metabolite has been administered in large doses to dogs with no apparent toxicity .…”

Blastocystis infection in patients with chronic renal disease

“…When appropriate, metronidazole can be used in patients with varying levels of renal disease, whether on dialysis or not [5].…”