Effect of Felbamate on Valproic Acid Disposition in Healthy Volunteers: Inhibition of β‐Oxidation

Abstract

We assessed the effects of felbamate (FBM) on the disposition of valpr oic acid (VPA) in healthy volunteer men. Eighteen subjects received sodium VPA, 400 mg/day for 21 days. Plasma and urine samples were taken on day 7 to document the steady-state disposition of VPA alone. From day 8 to day 21, subjects received placebo or FBM at the following doses (mg/day): 1,200, 2,400, 3,000, or 3,600 (n = 2-4 per group). Many adverse events (AE) occurred from about day 10; 2 subjects dropped out and 1 continued on a reduced FBM dose. Pharmacokinetic studies were repeated on day 21 for the 16 subjects who completed the study. FBM was measured in plasma and urine by high-performance liquid chromatography (HPLC). VPA and its 2-en, 4-en, and 3-oxo metabolites in plasma, and VPA (nonconjugated and total), and its 3-oxo and 4-hydroxy metabolites in urine were measured by gas chromatography/mass spectrometry (GC/MS). Mean plasma FBM trough concentrations on day 21 ranged from 26.9 mu g/ml (1,200 mg dose) to 76.8 mu g/ml (3,600-mg dose). Mean plasma VPA C max values were 32-42 mu g/ml in the various subgroups when VPA only was administered. Higher plasma VPA levels were observed when FBM was administered concurrently (55.4-63.8 mu g/ml). The excretion of 3-oxo-VPA in urine was significantly lower on day 21 than on day 7, whereas VPA-glucuronide was significantly increased. The effects of FBM on VPA disposition were dose dependent and were maximal at approximately 2400 mg/day. FBM has caused significant inhibition of the beta-oxidation pathway for VPA metabolic clearance, and this had been largely compensated by increased VPA glucuronidation.

Urinary excretion of valproate metabolites in children and adolescents

“…Following alkaline hydrolysis the urine was analysed for VPA, 4-hydroxy-valproate (4-OH-VPA) and 3-oxo-valproate (3-oxo-VPA) and the serum was analysed for VPA, 3-oxo-VPA and 2-en-valproic acid (2-en-VPA) by capillary gas chromatography methods described in more detail elsewhere [7,8]. The serum sample was also analysed for follicle stimulating hormone (FSH), luteinizing hormone (LH), prolactin, oestradiol, progesterone, testosterone and sex hormone binding globulin in the Chemical Pathology Laboratories of the Royal Brisbane Hospital using commercially available methods.…”

Abolition of Valproate-Derived Choleresis in the Mrp2 Transporter-Deficient Rat

“…Analysis of VPA and VPA-G in plasma, bile, and urine was performed by minor modification of the validated methods described previously (Dickinson et al, 1979;Hooper et al, 1996). Briefly, 150 l of water, 100 l of internal standard (nonanoic acid 500 g/ml of water), and a solution of 4 M NaCl/1 M HCl was added to 50 l of plasma, bile, or urine to a final volume of 800 l. After mixing (vortex, 30 s) VPA was extracted into 800 l of chloroform.…”

The Importance of Drug Interactions in Epilepsy Therapy

“…The exact clinical significance of this interaction is not known. This is the first report of an interaction in which the metabolism of VPA is inhibited (the ␤-oxidation pathway is inhibited) (94), and this may represent a potential target for interactions with new AEDs that are presently undergoing development. FBM is associated with numerous clinically significant interactions with a variety of AEDs.…”