Effects of carbamazepine on valproic acid kinetics in normal subjects

Carbamazepine and valproic acid are used together in the treatment of epilepsy. It is therefore, relevant to investigate the possibility of a carbamazepine effect on valproic acid disposition, particularly since carbamazepine is known to induce enzymes. We gave valproic acid orally to 6 normal subjects, 250 mg twice daily for 4 wk. Carbamazepine, 200 mg once daily, was begun after 4 days on valproic acid. Serum drug concentrations were measured during 4 dosing intervals, once before and 3 times after beginning carbamazepine. Minimum steady-state concentrations of valproic acid declined after carbamazepine from 34.4 +/- 5.1 to 27.1 +/- 4.4 mug/ml (p less than 0.0005). Clearance rose from 6.46 +/- 0.80 to 8.48 +/- 2.28 ml/hr/kg (p less than 0.01). The increase in clearanace and decrease in minimum steady-state levels was apparent only after 2 wk on carbamazepine. The elimination rate constant (KE) during the dosing interval did not rise during carbamazepine administration (0.0623 +/- 0.0168 hr--1 before and 0.0573 +/- 0.0168 hr--1 after, p greater than 0.25), raising the possibility of an increase in distribution volume.