MODIFICATION OF PHENYTOIN CLEARANCE BY VALPROIC ACID IN NORMAL SUBJECTS

1 The effect of valproic acid on the distribution and elimination kinetics of intravenously administered phenytoin has been investigated in eight normal volunteers. 2 In each of the subjects studied the volume of distribution of phenytoin increased significantly during treatment with sodium valproate (1200 mg daily for 7 days). 3 Phenytoin clearance was markedly increased in presence of valproic acid as compared to control values (0.52 +/‐ 0.17 v 0.38 +/‐ 0.11 ml min‐1 kg‐1 respectively, P less than 0.02). 4 It is suggested that the increase of the volume of distribution and of the serum clearance are secondary to displacement of phenytoin from plasma protein binding sites by valproic acid. 1979 The British Pharmacological Society