EFFECT OF FELBAMATE ON THE PLASMA-PROTEIN BINDING OF VALPROATE

Coadministration of felbamate is known to raise plasma valproate conce ntrations. In an attempt to explain this interaction, the effect of fe lbamate (FBM) on the plasma protein binding of valproate (VPA) was inv estigated in vitro and in healthy subjects. In fresh drug-free human p lasma spiked with 20.0, 60.0 and 100.0 mg Na VPA/L without and with 75 .5 mg FBM/L, the overall mean (+/- SD) unbound VPA fraction was 10.3 /- 1.6% without and 11.7 +/- 2.1% with FBM. Regression analysis, used to distinguish FBM effects on plasma protein binding from effects due to altered total VPA concentration (VPA shows concentration-dependent protein binding), indicated that the mean percentage unbound VPA rose by 1.44% (95% CI = 0.59 to 2.30%). In 12 subjects the mean (+/- SD) tr ough concentrations of total VPA in plasma rose from 21.0 +/- 6.1 mg/L to 45.1 +/- 9.5 mg/L (p < 0.01) when VPA was taken, and the overall m ean (+/- SD) unbound VPA fraction increased from 10.5 +/- 0.77% to 11. 7 +/- 1.17%. Regression analysis indicated that there was a mean incre ase of 0.68% (95% CI = 0.13 to 1.23%) in plasma-unbound VPA because of a direct effect of FBM on plasma protein binding, the remaining 0.5% increase being due to the altered VPA concentration. While FBM appears to displace VPA from plasma proteins, this interaction is small and u nlikely to make any important contribution to the overall effect of ad ding FBM to VPA, although the total interaction between the two may be large enough to necessitate a lowering of VPA dose.