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Effect of Felbamate on Valproic Acid Disposition in Healthy Volunteers: Inhibition of β‐Oxidation
Author(s) -
Hooper W. D.,
Franklin M. E.,
Glue P.,
Banfield C. R.,
Radwanski E.,
McLaughlin D. B.,
McIntyre M. E.,
Dickinson R. G.,
Eadie M. J.
Publication year - 1996
Publication title -
epilepsia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.687
H-Index - 191
eISSN - 1528-1167
pISSN - 0013-9580
DOI - 10.1111/j.1528-1157.1996.tb00518.x
Subject(s) - pharmacokinetics , urine , felbamate , glucuronide , chemistry , volunteer , valproic acid , anticonvulsant , metabolite , pharmacology , high performance liquid chromatography , placebo , chromatography , medicine , epilepsy , biochemistry , alternative medicine , pathology , psychiatry , agronomy , biology
Summary: We assessed the effects of felbamate (FBM) on the disposition of valproic 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 (GUMS). Mean plasma FBM trough concentrations on day 21 ranged from 26.9 μg/ml (1,200 mg dose) to 76.8 μg/ml (3,600–mg dose). Mean plasma VPA C max values were 32–42 μg/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 μg/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 ∼2400 mg/day. FBM had caused significant inhibition of the β‐oxidation pathway for VPA metabolic clearance, and this had been largely compensated by increased VPA glucuronidation.