Abstracts

We assessed whether the antiepileptic and chemotherapeutic drug valproic acid (VPA), an HDAC inhibitor, can induce P-gp expression in rat liver and brain. Additionally, we determined the effect of multi-day VPA administration on the anticonvulsant activity of the P-gp substrate phenytoin (PHT) and on its serum and brain concentrations., Mdr1a, mdr1b and mdr2 were determined by real-time polymerase-chain-reaction in rats treated for 2 or 7days with 1mmol/kg VPA, valpromide (VPD) or vehicle. The in vitro effect of VPA on P-gp was analyzed by flow cytometry. PHT anticonvulsant activity was determined in the maximal electroshock (MES) seizure test; results were compared to those obtained in a non-induced, vehicle-treated control group. PHT concentrations were assessed by high-performance-liquid-chromatography., Treatment of rats for 2 or 7 days with VPA increased liver expression of mdr1a (2.2- and 4.1-fold, respectively), and mdr2 (2.8- and 3.5-fold, respectively), but not mdr1b. VPA did not significantly alter the expression of either mdr isoform in rat hippocampus or cortex. Similarly, administration of VPD to rats did not increase P-gp mRNA expression in rat liver or brain. The effect of a series of VPA derivatives on P-gp expression in SW620, KG1a and MDCK cells correlated with their potency as HDAC inhibitors. Treatment with either VPA or VPD did not alter PHT serum or brain concentrations or compromise its anticonvulsant efficacy against tonic-extension seizures in the MES Test., VPA induces the expression of P-gp mRNA in rat livers. However, P-gp induction by VPA is not sufficient, under the treatment conditions employed, to alter the plasma or brain concentrations and anticonvulsant activity of the P-gp substrate PHT. Based on the results obtained in the present study, it is not likely that chronic treatment with VPA or VPD will modify the anticonvulsant efficacy of PHT by increasing PgP expression., (Supported by unrestricted funds of Profs. Bialer and NINDS Contract NO1-NS-4-2359 (HS White).)