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1 Plasma protein binding of phenytoin and of valproic acid were measured in ten epileptic patients on this drug combination. Ten other epileptics not on valproic acid served as controls. All patients had normal kidney function. 2 The measured free fraction of phenytoin among the patients on valproic acid ranged from 12.5 to 23.2% and after recalculation to a plasma albumin level of 45 g/l from 12.5 to 20.0 (median 15.4%). This differed significantly (P = 0.002, Mann- Whitney U-test) from the control patients where the normalized values ranged from 9.9 to 13.9% with a median value of 11.8%. 3 The measured free fractions of phenytoin and of valproic acid showed a significant correlation which, however, was due to the quantitative relation between the degree of binding of both these drugs and the concentration of plasma albumin. There was no discernable relation in this material between the free concentration of valproic acid and the free fraction of phenytoin. 4 It is concluded that patients on combined treatment with phenytoin and valproic acid have an unpredictably raised free fraction of phenytoin. This drug interaction therefore can complicate the important plasma level monitoring of phenytoin in epileptic patients unless the free concentration of this drug can be analysed or estimated.
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