Effect of sodium valproate on carbamazepine disposition and psychomotor profile in man.

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Abstract
1 The effect of sodium valoproate (VPA; 500 mg thrice daily for 7 days) and matched placebo on the disposition and psychomotor profile of a single dose of carbamazepine (CBZ; 10 mg kg-1) was studied in eight healthy male subjects using a randomised balanced crossover design. 2 VPA alone had no effect on antipyrine clearance, urinary 6.beta.-hydroxycortisol excretion and a battery of psychomotor function tests after 3 days'' treatment despite achieving a mean steady-state concentration (90 .+-. 6 mg l-1) well within the target range (50-100 mg l-1) for the drug. 3 VPA pre-treatment did not alter total CBZ area under the concentration-time curve (AUC 0-59 h) but did prolong CBZ elimination half life by 12% (P < 0.01). AUC 0-59 h for free plasma CBZ was 13% higher (P < 0.02) and half-life of unbound CBZ 16% longer (P < 0.02) during VPA treatment. CBZ-10,11 epoxide (CBZ-E) levels (52%) and CBZ-E/CBZ ratios (45%) were both elevated by concurrent VPA (P < 0.05) and free CBZ fraction was increased by 7% (P < 0.02). 4. The sole effect of VPA on the psychomotor profile of CBZ was prolongation of card sorting time (P < 0.05), although CBZ-related side effects were reported as more severe when VPA was also taken (P < 0.01). 5 These data suggest that VPA displaces CBZ from plasma protein binding sites and inhibits the metabolism of both the parent drug and its epoxide. The effect of VPA on the psychomotor profile of a large single dose of CBZ was minimal. 6 Further studies in epileptic patients receiving both these anticonvulsant drugs are warranted to appraise the extent and clinical relevance of their interaction.