Additional investigation on the potentiation of phenytoin teratogenicity by fluconazole

Fluconazole (FCZ) is a potent inhibitor of the cytochrome P450 (CYP)-mediated metabolism of the anti-epileptic agent phenytoin (PHT), a well-known human and animal teratogen. It has been postulated that phenytoin must be bioactivated via the CYP system to initiate teratogenesis. In contrast with this view, FCZ pretreatment has been previously shown to result in a potentiation of PHT teratogenesis. The current study was initiated to determine the impact of FCZ pretreatment on PHT exposure levels in maternal and embryonal compartments. HPLC analysis revealed that under a co-dosing FCZ–PHT regimen resulting in enhanced PHT teratogenesis, statistically significant higher PHT levels are detectable in maternal plasma and embryonic tissue in comparison to controls. These results further argue against a role for CYP system in teratogenic bioactivation of PHT.