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)‐warfarin, (S)‐mephenytoin, bufuralol, p‐nitrophenol, and carbamazepine as probes for CYPs 1A2, 2A6, 2C9, 2C19, 2D6, 2E1, and 3A4, respectively. Caffeine demethylation and the 6β‐hydroxycortisol/cortisol ratio were monitored in vivo before and after 14 days of treatment with stiripentol as measures of CYP1A2 and CYP3A4 activity, and dextromethorphan O‐ and N‐demethylation were used to measure CYP2D6 and CYP3A4 activity, respectively. In vivo inhibition constants for CYP3A4 were calculated with use of data that previously documented the interaction between stiripentol and carbamazepine. Results In vitro, stiripentol inhibited CYPs 1A2, 2C9, 2C19, 2D6, and 3A4, with inhibition constant values at or slightly higher than therapeutic (total) concentrations of stiripentol, but it did not inhibit CYPs 2A6 and 2E1 even at tenfold therapeutic concentrations. In vivo inhibition of caffeine demethylation and dextromethorphan N‐demethylation were consistent with inhibition of CYP1A2 and CYP3A4, respectively. The 6β‐hydroxycortisol/cortisol ratio did not provide a reliable index of CYP3A4 inhibition. Inhibition of CYP2D6‐mediated O‐demethylation was not observed in vivo. With use of carbamazepine, in vivo inhibition constants for CYP3A4 ranged between 12 and 35 μmol/L, whereas the corresponding in vitro value was 80 μmol/L. Conclusions Stiripentol appears to inhibit several CYP450 enzymes in vitro and in vivo. In vivo inhibition constants show that stiripentol inhibition of CYP3A4 is linearly related to plasma concentration in patients with epilepsy. Clinical Pharmacology & Therapeutics (1997) 62, 490–504; doi: