title: The relationship between glucuronide conjugate levels and hepatotoxicity after oral administration of valproic acid.
abstract: The aim of this study was to investigate the relationship between hepatotoxicity, levels of glucuronide conjugates of valproic acid (VPA), and the toxic metabolites of VPA (4-ene VPA and 2,4-diene VPA). We also examined whether hepatotoxicity could be predicted by the urinary excretion levels of VPA and its toxic metabolites. VPA was administrated orally in rats in amounts ranging from 20 mg/kg to 500 mg/kg. Free and total (free plus glucuronide conjugated) VPA, 4-ene VPA, and 2,4-diene VPA were quantified in urine and liver using gas chromatography-mass spectrometry. Serum levels of aspartate aminotransferase, alanine aminotransferase, and alpha-glutathione S-transferase (alpha-GST) were also determined to measure the level of hepatotoxicity. The serum alpha-GST level increased slightly at the 20 mg/kg dose, and substantially increased at the 100 and 500 mg/kg dose; aspartate aminotransferase and alanine aminotransferase levels did not change with the administration of increasing doses of VPA. The liver concentration of free 4-ene VPA and the urinary excretion of total 4-ene VPA were the only measures that correlated with the increase in the serum alpha-GST level (p < 0.094 and p < 0.023 respectively). From these results, we conclude that hepatotoxicity of VPA correlates with liver concentration of 4-ene VPA and can be predicted by the urinary excretion of total 4-ene VPA.
authors.affiliation: Bioanalysis and Biotransformation Research Center, Korea Institute of Science and Technology, Seoul, 136-791, Korea.
authors.forename: Min Sun
authors.initials: MS
authors.lastname: Lee
authors.forename: Young-Joo
authors.initials: YJ
authors.lastname: Lee
authors.forename: Bo Joon
authors.initials: BJ
authors.lastname: Kim
authors.forename: Kye Jung
authors.initials: KJ
authors.lastname: Shin
authors.forename: Bong Chul
authors.initials: BC
authors.lastname: Chung
authors.forename: Du-Jong
authors.initials: DJ
authors.lastname: Baek
authors.forename: Byung Hwa
authors.initials: BH
authors.lastname: Jung
mesh_terms: D000284:Administration, Oral; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D000927:Anticonvulsants / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity* / Q000652:urine; D001219:Aspartate Aminotransferases / Q000097:blood; D001711:Biotransformation; D056486:Chemical and Drug Induced Liver Injury; D004305:Dose-Response Relationship, Drug; D005229:Fatty Acids, Monounsaturated / Q000493:pharmacokinetics / Q000633:toxicity; D008401:Gas Chromatography-Mass Spectrometry; D005982:Glutathione Transferase / Q000097:blood; D007527:Isoenzymes / Q000097:blood; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008107:Liver Diseases / Q000378:metabolism; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D014635:Valproic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000493:pharmacokinetics* / Q000633:toxicity* / Q000652:urine
chemical_list: D000927:Anticonvulsants; D005229:Fatty Acids, Monounsaturated; D007527:Isoenzymes; C045022:2-propyl-4-pentenoic acid; C041285:valproic acid glucuronide; D014635:Valproic Acid; D005982:Glutathione Transferase; C119995:glutathione S-transferase alpha; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase