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Effects of ketoconazole on the polymorphic 4‐hydroxylations of S‐ mephenytoin and debrisoquine.
Author(s) -
Atiba JO,
Blaschke TF,
Wilkinson GR
Publication year - 1989
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1111/j.1365-2125.1989.tb05409.x
Subject(s) - ketoconazole , mephenytoin , debrisoquine , pharmacology , cyp3a , microsome , drug interaction , chemistry , enantiomer , pharmacokinetics , cytochrome p450 , medicine , cyp2d6 , in vitro , metabolism , cyp2c19 , biochemistry , stereochemistry , antifungal , dermatology
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.