Pharmacokinetic Profile of a New Anticonvulsant, Stiripentol, in the Rhesus Monkey

Abstract

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.

Stiripentol in Atypical Absence Seizures in Children: An Open Trial

“…Blood samples were obtained every 2 h, and serum was assayed for STP as previously described (Lin and Levy, 1983). The area under the concentration-time curve (AUC) was calculated by the trapezoidal rule.…”

Stiripentol – characteristic of a new antiepileptic drug

“…This particular characteristic resembles that of gentamicin [18] . Similarly, multiple phases for the plasma disappearance of stiripentol after intravenous application in monkeys have been observed [19] . Interestingly, some phases of the curves are rather a result of tissue distribution than elimination.…”

“…In the Rhesus monkey, the bioavailability of this AED is in the low range of 25 -28%, following oral or i.p. administration, and the drug has a very high protein binding [19] . Following intensive glucuronidation, stiripentol is eliminated in urine, the unchanged form being in a very low range [19] .…”

“…There has been a clear-cut dose-dependence regarding the elimination of this AED, speaking for nonlinearity. Specifically, for the dose range of 40 -120 mg/kg, the plasma clearance of stiripentol varied from 1.1 to 0.86 l/(h kg) in the Rhesus monkey [19] . By contrast, the volume of distribution of 1.03 l/kg and the mean residence time of 1.09 h have not been found to be dosedependent [19] .…”

“…Specifically, for the dose range of 40 -120 mg/kg, the plasma clearance of stiripentol varied from 1.1 to 0.86 l/(h kg) in the Rhesus monkey [19] . By contrast, the volume of distribution of 1.03 l/kg and the mean residence time of 1.09 h have not been found to be dosedependent [19] . Stiripentol easily passes through the bloodbrain barrier and its highest concentrations are encountered in the cerebellum and medulla oblongata in rats [17] .…”