title: Effect of felbamate on valproic acid disposition in healthy volunteers: inhibition of beta-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.
authors.affiliation: Department of Medicine, The University of Queensland Royal Brisbane Hospital, Brisbane, Australia.
authors.forename: W D
authors.initials: WD
authors.lastname: Hooper
authors.forename: M E
authors.initials: ME
authors.lastname: Franklin
authors.forename: P
authors.initials: P
authors.lastname: Glue
authors.forename: C R
authors.initials: CR
authors.lastname: Banfield
authors.forename: E
authors.initials: E
authors.lastname: Radwanski
authors.forename: D B
authors.initials: DB
authors.lastname: McLaughlin
authors.forename: M E
authors.initials: ME
authors.lastname: McIntyre
authors.forename: R G
authors.initials: RG
authors.lastname: Dickinson
authors.forename: M J
authors.initials: MJ
authors.lastname: Eadie
mesh_terms: D000328:Adult; D000927:Anticonvulsants / Q000493:pharmacokinetics* / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid; D004311:Double-Blind Method; D004347:Drug Interactions; D000078328:Felbamate; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D010084:Oxidation-Reduction; D048448:Phenylcarbamates; D010919:Placebos; D011409:Propylene Glycols / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D014635:Valproic Acid / Q000097:blood / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D000927:Anticonvulsants; D048448:Phenylcarbamates; D010919:Placebos; D011409:Propylene Glycols; D014635:Valproic Acid; D000078328:Felbamate