Valproic Acid: Interactions with Phenytoin and Phenobarbital

Abstract

VALPROIC ACID (VA) is a carboxylic acid derivative whose unique structure and pharmacologic activity have contributed to its popularity in the treatment of epilepsy. Although phenobarbital (PB) and phenytoin are still the mainstays of anticonvulsant therapy, refractory seizure disorders sometimes necessitate their combined use with VA. Combination therapy with VA frequently may result in improved seizure control; however, it also may result in valproate-mediated variations in the pharmacokinetics of both phenytoin and PB. The variations are such that they subsequently may result in toxicity from either of these two drugs. The purpose of this article is threefold: to review the proposed mechanism for the effect of VA on PB and phenytoin kinetics, to discuss the clinical significance of the interactions, and to identify patient management steps. Valproic Acid-Phenobarbital InteractionIn a randomized, crossover study of six normal subjects, mean PB elimination half-life was prolonged from 96 to 142 hours (p s 0.006) when VA steady-state plasma concentrations of 20-30 #Lg/ml (500 mg/d) were achieved. Mean PB plasma clearance was reduced from 4.2 to 3.0 mllh/kg (p s 0.009) and the calculated PB metabolic clearance was decreased from 3.3 to 2.0 mllh/kg (p s 0.005). Renal clearance of PB, urine pH, and PB volume of distribution did not change