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Pharmaceutisch Weekblad

, Volume 14, Issue 3, pp 146–151 | Cite as

Δ2-Valproate biotransformation using human liver microsomal fractions

  • Gérard Fabre
  • Christophe Briot
  • Eric Marti
  • Jean -Pierre Montseny
  • Martine Bourrié
  • Danielle Massé
  • Yves Berger
  • Jean -Paul Cano
Recent Developments on Valproate and its Metabolites

Abstract

The metabolism of 2-n-propyl-2-pentenoate (Δ2-VPA) was evaluated in human hepatic microsomal fractions. Two biotransformation pathways have been particularly investigated. In the presence of the cytochrome P-450 co-factor, NADPH, the main metabolites recovered were Δ3-VPA, Δ2,4-VPA and VPA. The glucuronidation of Δ2-VPA was also studied on various hepatic microsomal fractions using Brij® 35 as activator and UDP-glucuronic acid as co-factor. A large interindividual variability occurred in this metabolic pathway.K m andVmax were 0.85 mmol/l and 1.75 nmol·min−1·mg−1, respectively, for Δ2-VPA and 1.11 mmol/l and 5.71 nmol·min−1·mg−1 for VPA, respectively. The good correlationr=0.82; p<0.001) observed between the glucuronidation of VPA and Δ2-VPA as well as the mutual inhibition of each other's glucuronidation strongly suggests that (a) common single UDP-glucuronosyltransferase isoenzyme(s) was (were) involved in this glucuronidation step. The glucuronidation of specific substrates for various UDP-glucuronosyltransferase isoenzymes showed a good relationship between the glucuronidations of Δ2-VPA and morphine, a substrate for UDP-glucuronosyltransferase-2B. Moreover, morphine competitively inhibits A -VPA glucuronidation. It seems the same isoenzyme or, at least, (a) very closely related isoenzyme(s) belonging to UDP-glucuronosyltransferase-2 isoenzyme, is involved in Δ2-VPA glucuronidation.

Keywords

Biotransformation Cytochrome P-450 Isoenzymes Microsomes, liver 2-n-Propyl-2-pentenoic acid UDP glucuronosyltransferase Valproic acid 

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Copyright information

© Royal Dutch Association for Advancement of Pharmacy 1992

Authors and Affiliations

  • Gérard Fabre
    • 1
  • Christophe Briot
    • 1
  • Eric Marti
    • 1
  • Jean -Pierre Montseny
    • 1
  • Martine Bourrié
    • 1
  • Danielle Massé
    • 1
  • Yves Berger
    • 1
  • Jean -Paul Cano
    • 2
  1. 1.Sanofi RechercheMontpellier, Cédex 04France
  2. 2.Ministère Chargé de la SantéParis 07 SPFrance

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