Protection from Phenytoin‐Induced Congenital Malformations by Coadministration of the Antiepileptic Drug Stiripentol in a Mouse Model

Abstract

To test the hypothesis that the cytochrome P-450-inhibiting antiepileptic drug (AED) stiripentol (STP) can reduce the incidence of phenytoin (PHT) induced congenital malformations, we chronically administered the AEDs to three inbred mouse strains. The frequency of congenital defects in PHT-treated animals was dosage dependent, ranging from 7 to 55%. When STP was coadministered orally with PHT, there was a significant reduction in fetal defects in SWV and C57BL/6J mouse strains. A replication of the experiment was conducted with addition of a seventh group of mice that received the high dosage of PHT together with STP. In the replicate, all three strains demonstrated a significant reduction in fetal defects in fetuses exposed to PHT (60 mg/kg) and STP (200 mg/kg) as compared with PHT (60 mg/kg) monotherapy. These results strongly suggest that oxidative metabolites activated by cytochrome P-450 are the primary teratogenic molecules involved in PHT-induced teratogenesis and that clinical management of pregnant epileptic patients may be improved through heightened awareness of these drug interactions.

Investigations into Concurrent Exposure to Green Tea Extract and Phenytoin on the Incidence of Cleft Palate in CD-1 Mice

“…PHT is metabolized in the liver through cytochrome P450 enzymes, and in studies in which cytochrome P450 inhibitors were employed, the incidence of PHT-induced dysmorphogenesis was significantly reduced (Finnell et al 1994(Finnell et al , 1999. Green tea catechins (namely EGCG) have been found to inhibit some cytochrome P450 enzymes (Muto et al 2001).…”

Teratogene effekter av antiepileptika

“…Oksidativ metabolisering av antiepileptika er saerlig avhengig av cytochrom P450 isoenzymer som derved regulerer omsetningen av antiepileptika, men også produksjonen av bioaktive metabolitter som kan ha skadelige, evt. teratogene effekter (45)(46)(47)(48). Genetisk betingende forskjeller i cytochrom P450 isoenzym aktivitet kan forklare individuelle forskjeller i omsetning av enkelte antiepileptika og interaksjoner mellom antiepileptika.…”

“…Genetisk betingende forskjeller i cytochrom P450 isoenzym aktivitet kan forklare individuelle forskjeller i omsetning av enkelte antiepileptika og interaksjoner mellom antiepileptika. De kan også meget vel medvirke til genetiske forskjeller i teratogent potensiale av enkelte antiepileptika (45)(46)(47)(48). Stiripentol, et antiepileptikum som hemmer cytochrom P450, reduserer f.eks.…”

“…Stiripentol, et antiepileptikum som hemmer cytochrom P450, reduserer f.eks. forekomst av fenytoin-induserte misdannelser hos mus (47).…”

Treatment of epilepsy: existing therapies and future developments

“…Finnell et al (1994) demonstrated a significant reduction of the teratogenic effect of phenytoin in mice by the co-administration of stiripentol, an effect that could be explained in terms of reduced production of a teratogenic metabolite of phenytoin (473).…”