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

1 The effect of sodium valproate (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 1(-1)) well within the target range (50-100 mg 1(-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 less than 0.01). AUC 0-59 h for free plasma CBZ was 13% higher (P less than 0.02) and half-life of unbound CBZ 16% longer (P less than 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 less than 0.05) and free CBZ fraction was increased by 7% (P less than 0.02). 4 The sole effect of VPA on the psychomotor profile of CBZ was prolongation of card sorting time (P less than 0.05), although CBZ-related side effects were reported as more severe when VPA was also taken (P less than 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.(ABSTRACT TRUNCATED AT 250 WORDS)