A. Fazio

Sodium Valproate and Valpromide: Differential Interactions with Carbamazepine in Epileptic Patients

Summary: 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 < 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 pro‐drug 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.

A liquid chromatographic assay using a high-speed column for the determination of lamotrigine, a new antiepileptic drug, in human plasma.

A sensitive, specific and rapid liquid-chromatographic method for the determination of the new antiepileptic drug lamotrigine (LTG) in human plasma is described. The method involves the use of a commercially available 3-μm particle size normal-phase column and a microflow-cell-equipped ultraviolet detector. Extraction is carried out with ethyl acetate after alkalinization on a 100-μl plasma sample containing LTG and 3,5-diamino-6-(2-methoxyphenyl)-1,2,4-triazine as internal standard. The residue is reconstituted with 50 μl of ethanol, and 5 μl of the final solution is injected into the column. Elution is carried out at 35°C using n-hexane/absolute ethanol/35% ammonia (80/20/0.25 by volume) as mobile phase at a flow rate of 2.0 ml/min. Detection is at 313 nm. The chromatographic separation requires <3 min and the sensitivity limit is <0.1 mg/L. Recovery is 88–96.2%, whereas within-day and day-to-day coefficients of variation are between 4.1 and 7.7%.

Valproic acid-ethosuximide interaction: a pharmacokinetic study.

Summary: The present pharmacokinetic study was designed to investigate the possible interaction between valproic acid (VPA) and ethosuximide (ESM) in humans. Six drug‐free healthy volunteers, four men and two women, 18–42 years of age, received a single oral dose of 500 mg ESM before and during a treatment with VPA at 800‐ to 1,600‐mg daily doses. The second ESM dose was given 9 days after VPA administration was started. In this latter condition, a significant (p < 0.05) increase in ESM serum half‐life, from 44 to 54 h on average, and a significant (p < 0.05) decrease in total body clearance, from 11.2 to 9.5 ml/min on average, were observed. Other pharmacokinetic parameters were unchanged and showed values similar to those reported in the literature. Serum VPA levels ranged between 66.8 and 95 μg/ml. Two subjects showed no evidence of interaction. Although a great interindividual variability in the occurrence of VPA‐ESM interaction can be observed, the present study indicates that VPA is able to inhibit the metabolism of ESM. Possible factors affecting this interaction are hypothesized and discussed.

Single dose pharmacokinetics of carbamazepine-10,11-epoxide in patients on lamotrigine monotherapy

The pharmacokinetics of a single oral dose of carbamazepine-10,11-epoxide (CBZ-E, 100 mg) were compared in 10 patients on chronic monotherapy with lamotrigine (LTG, 200-300 mg/day) and in 10 drug-free healthy control subjects. CBZ-E pharmacokinetic parameters in LTG-treated patients were found to be similar to those observed in controls (half-life: 7.2 +/- 1.6 vs 6.1 +/- 0.9 h; apparent oral clearance: 110.8 +/- 53.1 vs 120.5 +/- 29.9 ml/h/kg; apparent volume of distribution: 1.08 +/- 0.37 vs 1.04 +/- 0.25 l/kg respectively; means +/- s.d.). These data indicate that, contrary to previous suggestions, LTG has no effect on the metabolic disposition of CBZ-E.

Interaction of carbamazepine-10.11-epoxide, an active metabolite of carbamazepine, with valproate : a pharmacokinetic study

Summary: The mechanism responsible for the valproate (VPA)‐induced elevation of serum carbamazepine‐10,11‐epoxide (CBZ‐E) levels was investigated in 6 normal subjects who received single oral doses of CBZ‐E (100 mg) in a control session and during concurrent treatment with sodium VPA [500 mg twice daily (b.i.d.)]. VPA caused a significant prolongation of CBZ‐E terminal half‐life (t± from 6.3 ± 1.2 to 9.0 ± 2.0 h, mean values ± SD) and decreased CBZ‐E clearance (from 90.6 ± 18.8 to 63.2 ± 16.1 ml h ‐1 kg‐1, mean values ± SD) without affecting CBZ‐E apparent volume of distribution (from 0.82 ± 0.19 to 0.81 ± 0.241 kg‐1, mean values ± SD). These findings indicate that VPA impairs the elimination of CBZ‐E, presumably by inhibiting its metabolism.

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,ll‐epoxide (CBZ‐E), increased fivefold from 1.5 ± 0.7 μg/ml at baseline to 7.4 ± 4.4 μg/ml after 4 days of VCD therapy and 7.7 ± 3.1 ^g/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 mi‐crosome preparations. Thus, VCD is a potent inhibitor of microsomal epoxide hydrolase (IC50 15 μM). 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.

Carbamazepine-viloxazine interaction in patients with epilepsy.

In 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.

Effect of Viloxazine on Serum Carbamazepine Levels in Epileptic Patients

Summary: The present study describes the interaction between carbamazepine (CBZ) and viloxazine, a recently synthesized antidepressant agent. Seven epileptic patients on chronic anticonvulsant therapy showed a significant (p <0.005) increase in steady‐state serum CBZ levels (from 8.1 ± 2.5 SD to 12.1 ± 2.5 SD μg/ml) when viloxazine (300 mg/day) was added to the therapy. The effect was associated with the appearance of mild CBZ intoxication. The symptoms of this intoxication (i.e., dizziness, ataxia, fatigue, drowsiness) disappeared rapidly, and serum CBZ levels decreased to the basal values, when viloxazine administration was stopped.

Effects of the antidepressant drug viloxazine on oxcarbazepine and its hydroxylated metabolites in patients with epilepsy

The effects of Viloxazine (VLX, 100 mg b.i.d. for 10 days) on the steady‐state plasma concentrations of Oxcarbazepine (OXC), its active metabolite 10,11‐dihydro‐10‐hydroxy‐carbazepine (MHD) and the corresponding diol (DHD) were studied in a randomized, double‐blind cross‐over placebo‐controlled trial in 6 epileptic patients stabilized on a fixed dosage of OXC. Administration of VLX resulted in an 11% increase in the plasma concentration of MHD (p = 0.003) associated with a 31% fall in DHD levels (p = 0.0001). Plasma concentrations of unchanged OXC were unaffected by VLX. No changes in seizure frequency nor signs of drug toxicity were observed during the study. Although VLX may inhibit the conversion of MHD to the inactive diol, the interaction is unlikely to be of clinical significance.

ELEVATION OF PLASMA CARBAMAZEPINE CONCENTRATIONS BY KETOCONAZOLE IN PATIENTS WITH EPILEPSY

The effect of ketoconazole (200 mg/d orally for 10 days) on the plasma concentrations of carbamazepine (CBZ) and its active metabolite carbamazepine-10,11-epoxide (CBZ-E) was assessed in eight patients with epilepsy stabilized on CBZ therapy. Administration of ketoconazole was associated with a significant increase in plasma CBZ concentrations (from 5.6 +/- 1.9 to 7.2 +/- 2.9 micrograms/ml on day 10 [means +/- SD, P < 0.02]), whereas plasma concentrations of CBZ-E were unchanged. After ketoconazole was discontinued, plasma CBZ levels decreased to pretreatment values. This interaction was probably mediated by an inhibiting action of ketoconazole on cytochrome CYP3A4, the main enzyme responsible for CBZ metabolism.