Disposition and Metabolism of Metronidazole in Patients with Liver Failure

A pharmacokinetic study of metronidazole disposition was performed in 10 patients with severe liver disease, the majority of whom also had impaired renal function. Following a single intravenous dose, systemic clearance of metronidazole was decreased by 66% in patients compared with healthy controls (p < 0.001). The apparent volume of distribution for metronidazole was also decreased in patients (by 21%), but the greater effect on clearance resulted in the elimination half-life being prolonged 152%. Total urinary excretion of unaltered metronidazole was not reduced in patients compared with controls, and systemic clearance of metronidazole did not correlate with creatinine clearance. Hepatic production of hydroxymetronidazole [l-(2-hydroxyethyl)-2-hydroxymethyl-5-nitroim-idazole], the major oxidative metabolite of metronidazole, was significantly lowered in patients with liver failure. Peak plasma levels of this metabolite were lower, the time taken to achieve peak levels was longer and the area under the plasma concentration ± time curve (AUC0-25h) was reduced in patients compared to controls (p < 0.05). Similarly, urinary recovery of hydroxymetronidazole was lower in patients with liver disease while excretion of the other major oxy-metabolite, 1-acetic acid-2-methyl-5-nitroimidazole, appeared reduced to an even greater extent. Thus, while the presence of renal function impairment in a patient with cirrhosis indicates that metronidazole elimination is likely to be abnormal, the principal mechanism for delayed elimination is impaired hepatic drug metabolism rather than reduced renal clearance of metronidazole and its major metabolites.