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.

Products formed from the reaction of two chloroethylnitrosoureas in neutral aqueous solution have been identified and quantified. Mixture components recovered after a 1-h incubation period accounted for 75--85% of the starting nitrosourea. Approximately 65--85% of the reaction products were formed by an initial cleavage of the nitrosourea to the proposed intermediates 2-chloroethyl azohydroxide and an isocyanate and by subsequent hydrolytic reactions. A minor pathway, 5--10% of products, involves denitrosation of the nitrosourea with oxazoline formation. Stable isotope labeling and mass spectrometry have been used to determine the reaction sequence and product origins. Reaction product identification has been made using high-performance LC isolation and comparison with synthetic material.

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Stiripentol is a new anticonvulsant drug derived from phenyl-l-pentene-ol. One of its metabolites resulting from opening of the methylenedioxy ring also possesses anticonvulsant activity. This study undertook to define the overall pharmacokinetic profile of stiripentol in rhesus monkey prior to its efficacy evaluation. The experimental design included six treatments (three intravenous doses of 40, 80, and 120 mg; one oral dose of 80 mg; and two intraperitoneal doses of 80 and 120 mg) administered to five chaired rhesus monkeys in a randomized fashion. Sixteen plasma samples were obtained over 7 h and urine was collected for 24 h. A high-performance liquid chromatography assay was developed for the determination of stiripentol in plasma and urine (C8 reverse phase column and UV detection, lambda = 254 nm). The intravenous data revealed multiexponential behavior and therefore noncompartmental methods were used to describe the pharmacokinetics of stiripentol. Values for plasma clearances (L/h/kg) were 1.10 +/- 0.07 (40 mg), 0.92 +/- 0.08 (80 mg), and 0.86 +/- 0.15 (120 mg). The decrease in clearance with dose provided evidence of nonlinearity. The average mean residence time was 1.09 +/- 0.03 h. The average volume of distribution at steady state was 1.03 +/- 0.3 L/kg. The bioavailabilities obtained for the oral and intraperitoneal doses were consistent with first-pass effect predictions: 0.3 (oral), 0.32 (i.p. 80 mg), and 0.34 (i.p. 120 mg). The free fraction determined by equilibrium dialysis was less than 1%. The fraction of dose excreted unchanged in urine ranged between 0 and 3%. The metabolite with anticonvulsant activity could not be detected in plasma with any of the modes of administration. However, it was found in urine and accounted for 2% of the dose. The fraction metabolized by glucuronidation was 34.8 +/- 9.1%. The percentages of total amount of glucuronide excreted in the intervals 0-2, 2-4, 4-8, and 8-24 h were 70.6 +/- 6.2, 10.1 +/- 5.4, 13.6 +/- 5.1, and 5.7 +/- 3.1%. These findings suggested that the terminal phase was not associated with elimination but rather with drug distribution.