Side-Effects Induced by Carbamazepine-10, 11-Epoxide

114

1 Oxcarbazepine (OXC), the 10-keto analogue of carbamazepine (CBZ), has similar anticonvulsant efficacy and possibly improved patient tolerability. Unlike CBZ, it is metabolised by reduction and may not induce hepatic monooxygenase enzymes. 2 Serum concentrations of OXC and its active metabolite 10-OH-carbazepine (10-OH-CZ) were followed after a single 300 mg dose and during and after 300 mg OXC twice daily for 29 doses in eight healthy male volunteers. 3 Antipyrine metabolism, urinary 6-,-hydroxycortisol excretion, sex hormone binding globulin (SHBG) levels and circulating androgens were measured as indices of hepatic enzyme induction before, during and after treatment with OXC. 4 Elimination half-lives (mean ± s.e. mean) of 10-OH-CZ were unaltered by 2 weeks' therapy with OXC (before 11.3 ± 1.1 h; after 13.9 ± 3 h). Trough plasma concentrations of 10-OH-CZ at steady-state (31 ± 2.2 ,umol 1-1) were higher than predicted (16.5 + 4 ,umol 1-1).5 Antipyrine metabolism, urinary 6-13-hydroxycortisol excretion, SHBG levels and circulating androgens were unaltered by treatment with OXC. 6 OXC (600 mg daily) does not induce hepatic monooxygenase enzymes and so is likely to have more predictable dose-concentration relationships and to produce fewer physiological and pharmacological interactions than CBZ.

Section: Oxc and Metabolitesmentioning

confidence: 99%

Lack of enzyme induction with oxcarbazepine (600 mg daily) in healthy subjects.

Larkin

Mckee

Forrest

et al. 1991

114

“…The increase in CBZ-E concentrations during VPA treatment may also contribute, as both in animal models (Frigerio & Morselli, 1975) and in patients with in trigeminal neuralgia (Tomson & Bertillson, 1984), CBZ and CBZ-E appear to have equipotent pharmacological activity. CBZ-E may itself provoke neurotoxic symptoms similar to CBZ (Patsalos et al, 1985). Patients receiving large doses of CBZ may be particularly susceptible to such toxicity because of pre-existent high concentration of CBZ-E due to autoinduction of the epoxide-diol pathway Bertilsson et al, 1986).…”

Section: Analysesmentioning

confidence: 99%

Effect of sodium valproate on carbamazepine disposition and psychomotor profile in man.

Macphee

Mitchell

Wiseman

et al. 1988

1 The effect of sodium valproate (VPA; 500 mg thrice daily for 7 days) and matched placebo on the disposition and psychomotor profile of a single dose of carbamazepine (CBZ; 10 mg kg-1) was studied in eight healthy male subjects using a randomised balanced crossover design.2 VPA alone had no effect on antipyrine clearance, urinary 6p-hydroxycortisol excretion and a battery of psychomotor function tests after 3 days' treatment despite achieving a mean steady-state concentration (90 ± 6 mg 1-1) well within the target range (50-100 mg I-1) for the drug.3 VPA pre-treatment did not alter total CBZ area under the concentration-time curve (AUC 0-59 h) but did prolong CBZ elimination half life by 12% (P < 0.01). AUC 0-59 h for free plasma CBZ was 13% higher (P < 0.02) and half-life of unbound CBZ 16% longer (P < 0.02) during VPA treatment. CBZ-10, 11 epoxide (CBZ-E) levels (52%) and CBZ-E/ CBZ ratios (45%) were both elevated by concurrent VPA (P < 0.05) and free CBZ fraction was increased by 7% (P < 0.02). 4 The sole effect of VPA on the psychomotor profile of CBZ was prolongation of card sorting time (P < 0.05), although CBZ-related side effects were reported as more severe when VPA was also taken (P < 0.01). 5 These data suggest that VPA displaces CBZ from plasma protein binding sites and inhibits the metabolism of both the parent drug and its epoxide. The effect of VPA on the psychomotor profile of a large single dose of CBZ was minimal. 6 Further studies in epileptic patients receiving both these anticonvulsant drugs are warranted to appraise the extent and clinical relevance of their interaction.

“…Further, the primary pharmacologically active metabolite of CBZ, carbamazepine-10, l1-epoxide (CBZ-E), which has been implicated in CBZ toxicity (Patsalos et al, 1985) Table 1 shows the main clinical details of the patients. All patients were on CBZ-C mainten- ance therapy for at least 3 months prior to entering the study.…”

Section: Introductionmentioning

confidence: 99%

A comparative pharmacokinetic study of conventional and chewable carbamazepine in epileptic patients.

Patsalos

1990

Using an open substitution study design, conventional carbamazepine (Tegretol, CBZ‐C and a chewable carbamazepine formulation (Tegretol Chewtabs, CBZ‐CHEW) were compared in 12 patients with severe intractable epilepsy. During a dosing interval, no significant differences were observed with respect to trough or peak serum concentrations of CBZ and CBZ‐10,11‐epoxide (CBZ‐E), the active metabolite. The area under the serum CBZ concentration‐time curve for a dosing interval was (mean +/− s.e. mean) 146 +/− 10 mumols l‐1 h on CBZ‐ C and 143 +/− 9 mumols l‐1 h on CBZ‐CHEW. The two formulations, therefore, have a similar pharmacokinetic profile and could be used interchangeably in the management of patients with epilepsy.