Nilutamide inhibits mephenytoin 4-hydroxylation in untreated male rats and in human liver microsomes

1. The effects of nilutamide (an anti-androgen with a hydantoin moiety) on the 4-hydroxylation of mephenytoin were studied in rat liver microsomes. Nilutamide, at a concentration expected in human liver (100uM) during prolonged administration of nilutamide, inhibited by 40% mephenytoin (0-3 mM) 4-hydroxylase activity in liver microsomes from untreated male rats, but not in microsomes from untreated female rats, or in microsomes from dexamethasone-treated male or female rats.

2. Administration to male rats of nilutamide, in doses (20mg/kg i.p. twice daily) known to reproduce plasma concentrations observed in human therapeutics, decreased by 60% the 24?h urinary excretion of 4-hydroxymephenytoin after administration of mephenytoin (15mg/kg oral).

3. Nilutamide (100uM) markedly inhibited mephenytoin 4-hydroxylase activity in human liver microsomes. Inhibition kinetics were consistent with mixed inhibition. It is concluded that nilutamide inhibits mephenytoin 4-hydroxylase activity in untreated male rats and in human liver microsomes. It is suggested that inhibition is likely to occur in vivo in humans receiving therapeutic doses of nilutamide.