To evaluate the comparative effects of valproic acid (VPA) and valpromide (VPM) on plasma levels and protein binding of carbamazepine (CBZ) and CBZ-10,11-epoxide (CBZ-E), 12 adult epileptic patients stabilized on CBZ monotherapy were divided into two groups. One group (n = 6) received sodium valproate (1,100 mg/day) for 2 weeks, while the other group (n = 6) was given, for the same period, a dosage of VPM (1,200 mg/day) expected to produce VPA levels equivalent to those achieved with valproate. Plasma CBZ levels were not affected by either treatment. In the valproate-treated group, plasma CBZ-E levels increased by 101% (range, 29-238%) within 1 week of combined therapy (p less than 0.02) and returned to baseline values after VPA treatment was stopped. In the VPM-treated patients, the elevation of plasma CBZ-E levels was much greater. In this group, plasma CBZ-E increased by 330% (range, 110-864%), and this was associated in two patients with the appearance of adverse effects which subsided after reducing the VPM dosage. The plasma protein binding of CBZ and CBZ-E was not affected significantly by VPM or valproate therapy. Plasma VPA levels were similar in the two groups. It is concluded that VPM is not simply a prodrug of VPA. Although both VPA and VPM increase CBZ-E levels--probably by inhibiting the enzyme epoxide hydrolase--the interaction caused by VPM is of much greater magnitude and potential clinical significance.

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SUMMARYIn six depressed epileptic patients stabilised on carbamazepine therapy, addition of the antidepressant agent viloxazine (300 mg/day for three weeks) induced a marked (average 55%) increase in steady-state plasma carbamazepine concentration. The concentration of the active metabolite carbamazepine-10,11 -epoxide also increased during viloxazine therapy, but to a lesser extent (16%). In three patients, these effects were associated with symptoms of carbamazepine intoxication, which regressed rapidly when plasma carbamazepine and carbamazepine-10,11-epoxide levels returned to baseline values after discontinuation of viloxazine. In a seventh patient, viloxazine had to be discontinued after only two weeks because of severe side effects associated with a striking elevation of carbamazepine and carbamazepine 10,11 -epoxide levels (by 197% and 137% respectively). Although viloxazine appears to be one of the few antidepressants which can be used safely in patients with epilepsy these results indicate that the drug should be prescribed with great caution in subjects treated with carbamazepine. The mechanism of the interaction probably involves inhibition of the metabolism of both carbamazepine and its active epoxide metabolite.Viloxazine is a "second generation" antidepressant which shows anticonvulsant properties in some animal models of epilepsy.' A number of studies, recently reviewed by Edwards,2 3 provide evidence that clinically the drug is non-epileptogenic or at least less epileptogenic than conventional antidepressants and therefore could be used safely in depressed epileptic patients. A rational use of viloxazine in these patients, however, requires knowledge of its possible interactions with concurrently administered anticonvulsants.4In a previous paper,5 we reported that the addition of viloxazine to carbamazepine therapy induces an increase in serum carbamazepine levels leading to the development of carbamazepine intoxication in some patients. The present study was designed to characterise this interaction in greater detail. To this purpose, the behaviour of the active metabolite carbamazepine-10,1 -epoxide (carbamazepine E) was also investigated. Material and methods Seven hospitalised epileptic patients with depressive symptoms who had been on a constant dosage of carbamazepine for at least 2 months agreed to take part in the trial (table 1). Viloxazine was administered for 3 weeks on a thrice daily regimen (100 mg at 9.00, 13.00 and 18.00). The dosage of CBZ was maintained unchanged throughout the study.Plasma carbamazepine and carbamazepine-E levels were determined at weekly intervals before, during and after viloxazine treatment. Blood samples were collected in heparinised tubes before the first daily carbamazepine dose (9.00) and 3 hours later. The plasma was separated immediately and stored at -20°C until analysis. Carbamazepine and carbamazepine-E concentrations were determined by HPLC according to Milhaly et al6 with minor modifications (results given in the text are means of values at the t...

In order to evaluate the influence of chronic antiepileptic drug treatment on the kinetics of the antidepressant viloxazine (VLX), six drug-free control subjects and six epileptic patients treated with one or two anticonvulsants (phenobarbital, carbamazepine or phenytoin) were given a single oral dose of VLX (200 mg). On a separate occasion, the patients were also given 200 mg VLX by IV infusion. Plasma VLX levels were determined by GLC. Following oral dosing, VLX was rapidly absorbed from the gastrointestinal tract (peak levels at 0.5-4 h); plasma level profiles showed a considerable interindividual variability but did not differ significantly between patients and controls. Terminal half-lives were 4.3 +/- 1.5 h in the patients and 4.3 +/- 1.8 h in the controls. Clearance and volume of distribution calculated after IV dosing in the patients were 124 +/- 11 ml h-1 kg-1 and 0.73 +/- 0.28 l/kg, respectively. The absolute oral availability was 85 +/- 14%. At variance with findings reported for other antidepressants, VLX kinetics do not appear to be significantly altered by concurrent treatment with enzyme-inducing antiepileptic drugs.