Pharmacokinetics of stiripentol in normal man: evidence of nonlinearity

The pharmacokinetics and metabolism of stiripentol, a new antiepileptic drug, were investigated in normal male subjects after single-dose and multiple-dose administration. Each of six subjects received single doses of 300, 600, and 1200 mg of stiripentol in powder form and another 600 mg in solution. In the multiple-dose study, each of six subjects received a 300-mg dose on day 1 and multiple doses (1200 mg/day) from day 2 to day 8. Five of these six subjects participated also in the single-dose study. Stiripentol and several of its metabolites, namely, stiripentol conjugate, DiOH, P-OH, and M-OH, were analyzed in plasma and urine. After single doses, the elimination curve of stiripentol appeared multiphasic. The oral clearance was 1.3 to 1.8 liter/hr/kg. The average mean residence time was 4 hours. There were no statistically significant differences in clearance or mean residence time among the three doses. However, dose dependence was found in all the four pathways when formation clearances were compared. Only trace amounts of the drug were excreted unchanged in urine. The active metabolite, P-OH, was not detectable in plasma. Stiripentol was very highly bound to plasma proteins in plasma from dosed subjects as well as spiked human plasma (free fraction of 1 per cent). In the multiple-dose study, there was a decrease (nearly eightfold) in oral clearance of stiripentol between day 1 and day 8. The fractions of dose metabolized through conjugation and methylenedioxy ring opening increased 183 and 49 per cent, respectively, but the formation clearances for all the pathways were decreased. These findings suggest that the steady-state plasma level/dose ratio of stiripentol will increase with the daily dose.