DISTRIBUTION OF UNSATURATED METABOLITES OF VALPROATE IN HUMAN AND RAT-BRAIN - PHARMACOLOGICAL RELEVANCE

The concentrations of valproate (VPA) and six of its pharmacologically active, unsaturated metabolites (E-Delta(2)-VPA, Z-Delta(3)-VPA, E-De lta(3)-VPA, E,E-Delta(2,3')-VPA, Delta(4)-VPA, and E-Delta(2,4)-VPA) w ere measured in serum and cortical brain samples from 24 patients unde rgoing epilepsy surgery. Collectively, the six metabolites were presen t at concentrations <13% of VPA brain concentrations. Because the six unsaturated metabolites were present at such low brain concentrations, we concluded that these metabolites probably did not contribute signi ficantly to the anticonvulsant effect of VPA. Results from a parallel pharmacodynamic study in rats in which VPA was administered three time s daily for 8 weeks supported this conclusion. Only three unsaturated metabolites (E-Delta(2)-VPA, Delta(3)-VPA, E,E-Delta(2,3')-VPA) were d etected in rat brain. No correlation was observed between the time cou rse of anticonvulsant effect [as measured by the timed intravenous pen tylenetetrazol (PTZ) test] and the time course of VPA or metabolite co ncentrations in rat brain. Despite the structural similarity of VPA an d its metabolites, striking differences were observed in their serum p rotein binding and blood-brain distribution properties. In the human b rain, VPA and Delta(4)-VPA exhibited brain-to-free serum concentration ratios that were less than unity. In contrast, compounds with the dou ble bond at the 2- or 3-position had brain:free concentration ratios t hat were much higher than unity. The structure-distribution relationsh ip observed with VPA and its unsaturated metabolites suggested that th ese branched-chain fatty acids differ in their asymmetric transport ac ross the blood-brain barrier (BBB).