Effects of carbamazepine on valproic acid kinetics in normal subjects

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Abstract
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 µg/ml (p < 0.0005). Clearance rose from 6.46 ± 0.80 to 8.48 ± 2.28 ml/hr/kg (p < 0.01). The increase in clearance 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 > 0.25), raising the possibility of an increase in distribution volume.