Studies on the metabolic fate of valproic acid in the rat using stable isotope techniques

Abstract

1. The metabolic fate of two specifically deuterated analogues of valproic acid (VPA), [2-2H1]VPA and [3,3-2H2]VPA, was studied in the rat following i.p. injection. 2. A total of 11 urinary metabolites of each labelled substrate were detected by g.l.c.-mass spectrometry. Those metabolites which resulted from oxidation of the drug at C-4 and/or C-5 retained the deuterium label(s), whereas products of oxidation at C-2 and/or C-3 exhibited varying degrees of deuterium loss. 3. The deuterium content of 3-hydroxy-VPA indicated that this metabolite has a dual origin, and arises in part by beta-oxidation of VPA and in part by direct hydroxylation at C-3. An apparent intramolecular isotope effect (kH/kD) of ca. 8 was associated with the latter process. 3-Oxo-VPA appeared to be formed mainly by oxidation of delta 2-VPA, rather than by oxidation of 3-hydroxy-VPA. 4. Evidence was obtained that delta 3-VPA is formed reversibly from delta 2-VPA, and that further desaturation of delta 3-VPA gives rise to a metabolite believed to have a 2,3'-diene structure. 5. The stable isotope method employed in this investigation represents a powerful technique for studies on the origin of drug metabolites and for the elucidation of complex metabolic inter-relationships in vivo.

Altered Pharmacokinetics and Metabolism of Valproate after Replacement of Conventional Valproate with the Slow‐Release Formulation in Epileptic Patients

“…Two‐en is formed by mitochondrial β‐oxidation of valproate. It has been shown that 3‐en is reversibly formed by isomerization of 2‐en (Rettenmeier et al 1987). Both 2‐en and 3‐en are relatively major metabolites in human serum, which probably reflect β‐oxidative metabolism of valproate in mitochondria.…”

Valproic acid metabolism and its effects on mitochondrial fatty acid oxidation: A review

“…The three products represented three VPA b-oxidation intermediates. Further studies on VPA metabolites formed in vivo (Jakobs and Lö scher 1978;Lö scher et al 1981;Nau and Lö scher 1982;Nau et al 1981Nau et al , 1984Rettenmeier et al 1987) reinforced the idea that b-oxidation is a major oxidative pathway of VPA metabolism.…”

β‐Oxidation of Valproic Acid.

“…1989 olite is generally believed to arise as an intermediate in the possible P-oxidation of VPA. Recent evidence indicates that this metabolite is formed by P,,,-dependent a,-oxidation (Prickett and Baillie, 1984) in addition to apparent @-oxidation (Rettenmeier et al, 1987), which seriously limits reliance o n this metabolite as a n indication of VPA (3oxidation. The observed absence of an effect on this metabolite further appears to disqualify it in this regard.…”