Carbamazepine-valnoctamide interaction in epileptic patients: in vitro/in vivo correlation

Six patients stabilized with carbamazepine (CBZ) therapy received an 8-day "add-on" supplement of valnoctamide (VCD), a tranquilizer available over the counter (OTC) in several European countries that exhibits promising anticonvulsant activity in animal models. During VCD intake, serum levels of the active CBZ metabolite, carbamazepine-10,11-epoxide (CBZ-E), increased fivefold from 1.5 +/- 0.7 micrograms/ml at baseline to 7.4 +/- 4.4 micrograms/ml after 4 days of VCD therapy and 7.7 +/- 3.1 micrograms/ml after 7 days of VCD therapy (means +/- SD, p < 0.01). In 4 patients, the increase in serum CBZ-E levels was associated with clinical signs of CBZ intoxication. CBZ-E levels returned to baseline after VCD therapy was discontinued. Serum CBZ levels remained stable throughout the study. The interaction observed in this study is similar to that described in patients treated with CBZ and valpromide (VPD, an isomer of VCD). In a mechanistic study, therapeutic concentrations of VCD inhibited hydrolysis of styrene oxide in human liver microsome preparations. Thus, VCD is a potent inhibitor of microsomal epoxide hydrolase (IC50 15 microM). There was a striking similarity between in vitro and in vivo inhibition potencies. In this study, VCD clearance was higher in epileptic patients (treated with CBZ) than in healthy subjects.