Effect of inducers and inhibitors of glucuronidation on the biliary excretion and choleretic action of valproic acid in the rat

J. B. Watkins, C. D. Klaassen

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Abstract

Valproic acid (VPA) induces an immediate choleresis in the rat which may be attributable to the osmotic properties of VPA-glucuronic acid conjugates in bile. The influence of inducers and inhibitors of glucuronidation of VPA on the biliary excretion and choleretic effect of VPA was studied. Hepatic UDP-glucuronyltransferase activity toward VPA was determined in vitro. Pretreatment with phenobarbital (75 mg/kg/day for 4 days) enhanced VPA glucuronidation; borneol (750 mg/kg) decreased VPA conjugation; 3-methylcholanthrene (20 mg/kg/day for 4 days) and galactosamine (600 mg/kg) had no effect on glucuronidation of VPA in vitro. Hepatic UDP-glucuronic acid content was decreased by borneol and galactosamine administration and was enhanced by phenobarbital and 3-methylcholanthrene pretreatment. The enzyme inducers increased the plasma disappearance of VPA in vivo but did not augment its biliary excretion or choleretic effect. Borneol and galactosamine, which inhibited the conjugation and plasma disappearance of VPA, decreased its biliary excretion and inhibited the VPA-induced increase in bile flow. Thus, the bile flow rate after VPA administration is closely related to the excretion of VPA-glucuronic acid. These data support the conclusion that the choleretic effect of VPA is due to the osmotic activity of VPA conjugates in bile.

Original languageEnglish (US)
Pages (from-to)305-310
Number of pages6
JournalJournal of Pharmacology and Experimental Therapeutics
Volume220
Issue number2
StatePublished - 1982
Externally publishedYes

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Cholagogues and Choleretics
Valproic Acid
Bile
Galactosamine
Glucuronic Acid
Methylcholanthrene
Hepatobiliary Elimination
Phenobarbital
Uridine Diphosphate Glucuronic Acid
Glucuronosyltransferase
Uridine Diphosphate
Liver

ASJC Scopus subject areas

  • Pharmacology

Cite this

Effect of inducers and inhibitors of glucuronidation on the biliary excretion and choleretic action of valproic acid in the rat. / Watkins, J. B.; Klaassen, C. D.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 220, No. 2, 1982, p. 305-310.

Research output: Contribution to journalArticle

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