Under aerobic conditions the hepatic clearance of nitrofurantoin is rather low (1 ml/min) indicating only a minor role of the liver for the overall elimination of this drug under in vivo conditions. In the presence of ethanol (38 mM) the clearance of nitrofurantoin was accelerated significantly (2 ml/min) suggesting an ethanol-mediated reductive metabolism even under aerobic conditions. The hepatic oxygen uptake was enhanced by nitrofurantoin in a dose-dependent manner and reached 160% of the control rate (1.4 mol O₂×g^–1×min^–1) at 0.2 mM nitrofurantoin. This effect may indicate the formation of active oxygen species in the intact organ.

4-Hydroxylation of nitrofurantoin could only be detected after induction with -naphthoflavone or 3-methylcholanthrene. The hepatic clearance of nitrofurantoin was raised to 3–4 ml/min after pretreatment with these agents which are known to induce the same group of cytochromes P-450. Hepatic clearance and hydroxylation rates after induction with 3-methylcholanthrene were found to be strongly correlated. Metyrapone (0.1 mM) and -naphthoflavone (0.1 mM) inhibited the 4-hydroxylation of nitrofurantoin by 90 and 100%, respectively. The aerobic microsomal metabolism of nitrofurantoin was also enhanced by induction with 3-methylcholanthrene. The results indicate that 4-hydroxylation of nitrofurantoin is catalyzed by a 3-methylcholanthrene-inducible form of cytochrome P-450.