Delta 2-valproate biotransformation using human liver microsomal fractions.
The metabolism of 2-n-propyl-2-pentenoate (delta 2-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 delta 3-VPA, delta 2,4-VPA and VPA. The glucuronidation of delta 2-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. Km and Vmax were 0.85 mmol/l and 1.75 nmol.min-1.mg-1, respectively, for delta 2-VPA and 1.11 mmol/l and 5.71 nmol.min-1.mg-1 for VPA, respectively. The good correlation (r = 0.82; p less than 0.001) observed between the glucuronidation of VPA and delta 2-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 delta 2-VPA and morphine, a substrate for UDP-glucuronosyltransferase-2B. Moreover, morphine competitively inhibits delta 2-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 delta 2-VPA glucuronidation.
Fabre
G
G
Sanofi Recherche, Montpellier, France.
Briot
C
C
Marti
E
E
Montseny
J P
JP
Bourrié
M
M
Massé
D
D
Berger
Y
Y
Cano
J P
JP
D000927:Anticonvulsants / Q000493:pharmacokinetics*; D001711:Biotransformation; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D005229:Fatty Acids, Monounsaturated / Q000493:pharmacokinetics*; D008401:Gas Chromatography-Mass Spectrometry; D014453:Glucuronosyltransferase / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D008862:Microsomes, Liver / Q000378:metabolism*; D010105:Oxygenases / Q000378:metabolism
D000927:Anticonvulsants; D005229:Fatty Acids, Monounsaturated; C014168:2-propyl-2-pentenoic acid; D003577:Cytochrome P-450 Enzyme System; D010105:Oxygenases; D014453:Glucuronosyltransferase