6533b859fe1ef96bd12b783a

RESEARCH PRODUCT

Reductive and oxidative metabolism of nitrofurantoin in rat liver.

subject

description

The elimination of nitrofurantoin was studied in the isolated rat liver using a recirculating hemoglobin-free perfusion system. The most rapid clearance of nitrofurantoin (0.1 mM) was found under hypoxia (8 ml/min) or anoxia (11 ml/min) indicating a fast and oxygen-sensitive reductive metabolism. The hepatic elimination of nitrofurantoin under anaerobic conditions apparently is not catalyzed by xanthine oxidase, aldehyde oxidase or cytochrome P-450 as judged from the lack of influence of the inhibitors (0.1 mM) allopurinol, menadione, metyrapone, α-naphthoflavone or of carbon monoxide (50%; v/v). 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 μmol 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 β-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 α-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.