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 less than 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 [1-(2-hydroxyethyl)-2-hydroxymethyl-5-
nitroimidazole], 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 approximately time curve (AUC0-25h) was reduced in patients compared to controls (p less than 0.05). Similarly, urinary recovery of hydroxymetronidazole was lower in patients with
liver disease while excretion of the other major oxymetabolite,
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.