Effects of ketoconazole on the polymorphic 4-hydroxylations of S-mephenytoin and debrisoquine.

Studies were undertaken in 12 normal, male subjects to determine whether a metabolic interaction occurs between ketoconazole and mephenytoin. A single dose (400 mg) of ketoconazole produced a reduction in the 0-8 h urinary R/S ratio of mephenytoin following oral administration (100 mg) of racemic drug and after 28 daily doses the median value was further reduced to 42.9% of its baseline value. Within 7 days following discontinuation of ketoconazole the enantiomeric ratio had returned to its pre-study value. These findings are consistent with ketoconazole being a potent in vivo inhibitor of mephenytoin's 4-hydroxylation and confirm the ability of such an interaction to be predicted by in vitro studies with human liver microsomes. By contrast, ketoconazole had a much smaller effect on the 0-8 h urinary metabolic ratio of debrisoquine, indicating that ketoconazole has a selective inhibitory effect on different forms of cytochrome P-450.