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 avail able over the counter (OTC) in several European countries that exhibit s promising anticonvulsant activity in animal models. During VCD intak e, serum levels of the active CBZ metabolite, carbamazepine-10,11-epox ide (CBZ-E), increased fivefold from 1.5 +/- 0.7 mug/ml at baseline to 7.4 +/- 4.4 mug/ml after 4 days of VCD therapy and 7.7 +/- 3.1 mug/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 thera py was discontinued. Serum CBZ levels remained stable throughout the s tudy. The interaction observed in this study is similar to that descri bed 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. Th us, VCD is a potent inhibitor of microsomal epoxide hydrolase (IC50 15 muM). There was a striking similarity between in vitro and in vivo in hibition potencies. In this study, VCD clearance was higher in epilept ic patients (treated with CBZ) than in healthy subjects.