INFLUENCE OF STIRIPENTOL ON CYTOCHROME P450-MEDIATED METABOLIC PATHWAYS IN HUMANS - IN-VITRO AND IN-VIVO COMPARISON AND CALCULATION OF IN-VIVO INHIBITION CONSTANTS

Objective: The spectrum of cytochrome P450 inhibition of stiripentol, a new anticonvulsant, was characterized in vitro and in vivo. Methods: Stiripentol was incubated in vitro with (R)-warfarin, coumarin, (S)-w arfarin, (S)-mephenytoin, bufuralol, p-nitrophenol, and carbamazepine as probes for CYPs 1A2, 2A6, 2C9, 2C19, 2D6, 2E1, and 3A4, respectivel y. Caffeine demethylation and the 6 beta-hydroxycoaisol/cortisol ratio were monitored in vivo before and after 14 days of treatment with sti ripentol as measures of CYP1A2 and CYP3A4 activity, and dextromethorph an O- and N-demethylation were used to measure CYP2D6 and CYP3A4 activ ity, respectively. In vivo inhibition constants for CYP3A4 were calcul ated with use of data that previously documented the interaction betwe en stiripentol and carbamazepine. Results: In vitro, stiripentol inhib ited CYPs 1A2, 2C9, 2C19, 2D6, and 3A4, with inhibition constant value s at or slightly higher than therapeutic (total) concentrations of sti ripentol, but it did not inhibit CYPs 2A6 and 2E1 even at tenfold ther apeutic concentrations. In vivo inhibition of caffeine demethylation a nd dextromethorphan N-demethylation were consistent with inhibition of CYP1A2 and CYP3A4, respectively. The 6 beta-hydroxycortisol/cortisol ratio did not provide a reliable index of CYP3A4 inhibition. Inhibitio n of CYP2D6-mediated O-demethylation was not observed in vivo. With us e of carbamazepine, in vivo inhibition constants for CYP3A4 ranged bet ween 12 and 35 mu mol/L, whereas the corresponding in vitro value was 80 mu mol/L. Conclusions: Stiripentol appears to inhibit several CYP45 0 enzymes in vitro and in vivo. In vivo inhibition constants show that stiripentol inhibition of CYP3A4 is linearly related to plasma concen tration in patients with epilepsy.