4-Hydroxylation of nitrofurantoin in the rat. A 3-methylcholanthrene-inducible pathway of a relatively nontoxic compound.

When nitrofurantoin was administered daily to rats, the urinary excretion of unmetabolized drug was significantly decreased after induction by 3-methylcholanthrene or beta-naphthoflavone, but was not altered after treatment with phenobarbital. In urine samples taken 36 hr after a single dose of 14C-nitrofurantoin in rats induced with 3-methylcholanthrene, the total excretion of radioactivity (30% of dose) was the same as in noninduced rats. The proportion of unchanged nitrofurantoin, however, was only 33% of the radioactivity recovered in urine from 3-methylcholanthrene-treated animals whereas in urine from control animals 76% of the activity could be attributed to the unmetabolized drug. In 6-hr urine samples one metabolite was present to a detectable extent only in urine from 3-methylcholanthrene-treated animals. The metabolite was identified as the 4-hydroxy derivative of nitrofurantoin. 4-Hydroxylation of nitrofurantoin may find use as indicator reaction for a 3-methylcholanthrene-type induction state under in vivo conditions.