This study was designed to assess the effects of felbamate, a new anti-convulsant, on the disposition of 2-propylpentanoic acid (valproic acid, VPA), an established anticonvulsant, in volunteers at steady state. Healthy male volunteers (18) were administered sodium valproate, 400 mg/day for 21 days. Plasma and urine samples were to be collected on Day 7 to document the steady state disposition of valproate taken alone. From Day 8 subjects were to receive felbamate in addition to valproate at doses of 1200, 2400, 3000 or 3600 mg/day, or placebo. Plasma and urine samples were to be collected on Day 21 to document the disposition of valproate taken with felbamate an of felbamate itself. Felbamate was measured in plasma and urine samples by HPLC. VPA, (E)-2-en-VPA, 4-en-VPA and 3-oxo-VPA in plasma and VPA (non-conjugated and total), 3-oxo-VPA and 4-OH-VPA in urine were measured by GC-MS. Plasma and/or urine samples were spiked with the internal standard, nonanoic acid, and treated by solvent extraction. The analytes were resolved on a 25 m length of 0.2 mm ID HP- FFAP capillary column within 10 min. The MS detector was programmed to monitor a separate SIM group for each of the analytes, using a minimum of two ions per group. The analytes were quantitated within the range of 0.1-500 µg/ml plasma and/or urine.

Mean plasma felbamate trough concentrations on Day 21 ranged from 26.9 µg/ml (1200 mg/day) to 76.8 µg/ml (3600 mg/day). Mean plasma VPA C_max values were between 32 - 42 µg/ml in the various subgroups. Higher plasma VPA C_max values were observed when felbamate was taken concurrently (55.4 to 63.8 µg/ml). The effect of felbamate on VPA C_max and AUC values was lower at 1200 mg/day than at 2400 mg/day or above. The plasma valproate metabolite data suggested that felbamate inhibited ß-oxidation of valproate. This was supported by the data for urinary metabolites of valproate, which showed diminished excretion of 3-oxo-VPA in all subjects taking felbamate plus valproate, in comparison with VPA taken alone. This reduction was at least partly compensated by increased urinary excretion of VPA-glucuronide. We concluded that felbamate had caused significant inhibition of the ß-oxidation pathway for valproate, which was largely compensated by increased valproate glucuronidation.