-transparent.png){kind=logo}
The influence of phenobarbital, clofibrate, 3-methylcholanthrene and beta-naphthoflavone on omega- and beta-oxidation as well as on glucuronidation of valproic acid (n-dipropylacetic acid) was evaluated in male Sprague-Dawley rats by determination of urinary excretion of its metabolites by GC-MS after administration of 100 mg/kg. In controls 12% of the dose was excreted within 24 hours, primarily as glucuronides; metabolites formed by oxidation amounted to about 4%. Phenobarbital treatment led to stimulation of 4-hydroxyvalproic acid [(omega-1)-oxidation], 5-hydroxyvalproic acid and n-propylglutaric acid (omega-oxidation) excretion. Clofibrate enhanced the excretion of 4-hydroxyvalproic acid and 3-keto-valproic acid, a product of peroxisomal beta-oxidation. beta-Naphthoflavone slightly increased the excretion of 5-hydroxyvalproic acid. The most specific effect was found for 3-methylcholanthrene, which was effective in stimulating the formation of 3-hydroxyvalproic acid which might be formed by (omega-2)-oxidation. The addition of fatty acids (olive oil in which 3-methylcholanthrene and beta-naphthoflavone were suspended) led to increased excretion of 3-keto-valproic, 4-hydroxyvalproic and n-propylglutaric acid. The excretion of 3-hydroxyvalproic acid was completely suppressed by olive oil. Such specific effects were not observed for glucuronidation of valproic acid and its metabolites, although stimulation was attained after phenobarbital, clofibrate and 3-methylcholanthrene treatment, because of instability of glucuronide conjugates. Stimulation of valproic acid metabolism was also shown by increased plasma clearance after treatment with phenobarbital. In contrast, clofibrate given once 1 hr before valproic acid inhibited excretion of valproic acid, possibly by competition during renal tubular secretion. Determination of valproic acid metabolites in urine provides a useful tool for evaluation of inducer specificity of short chain fatty acid metabolism and differentiation between microsomal and peroxisomal enzyme activity.
G Heinemeyer, and
H Nau, and
A G Hildebrandt, and
I Roots
March 1996,
Drug metabolism and disposition: the biological fate of chemicals,
G Heinemeyer, and
H Nau, and
A G Hildebrandt, and
I Roots
January 1982,
The Journal of biological chemistry,
G Heinemeyer, and
H Nau, and
A G Hildebrandt, and
I Roots
January 1990,
Zeitschrift fur Versuchstierkunde,
G Heinemeyer, and
H Nau, and
A G Hildebrandt, and
I Roots
February 1980,
Biochemical pharmacology,
G Heinemeyer, and
H Nau, and
A G Hildebrandt, and
I Roots
August 1996,
Toxicology,
G Heinemeyer, and
H Nau, and
A G Hildebrandt, and
I Roots
February 1994,
Biochemical pharmacology,
G Heinemeyer, and
H Nau, and
A G Hildebrandt, and
I Roots
April 1985,
Biochemical pharmacology,
G Heinemeyer, and
H Nau, and
A G Hildebrandt, and
I Roots
December 1993,
Toxicology and applied pharmacology,
G Heinemeyer, and
H Nau, and
A G Hildebrandt, and
I Roots
June 1983,
Biochemical pharmacology,
G Heinemeyer, and
H Nau, and
A G Hildebrandt, and
I Roots
January 1983,
Drug metabolism and disposition: the biological fate of chemicals,
