Verapamil Potentiates Carbamazepine Neurotoxicity: A Clinically Important Inhibitory Interaction

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.

Section: Analysesmentioning

confidence: 99%

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

Macphee

Mitchell

Wiseman

et al. 1988

“…Verapamil has been demonstrated to inhibit the clearances of antipyrine (Bauer et al, 1986;Rumiantsev et al, 1986) and carbamazepine (Macphee et al, 1986) in man. A case report suggests that verapamil may also inhibit theophylline clearance (Burnakis et al, 1983).…”

Section: Introductionmentioning

confidence: 99%

Selective inhibitory effects of nifedipine and verapamil on oxidative metabolism: effects on theophylline.

Robson

Miners

Birkett

1988

Nine healthy male volunteers were studied to assess the possibility of an interaction between theophylline and nifedipine or verapamil using axrandomised, crossover design. Subjects received theophylline 125 mg 8 hourly with and without nifedipine 20 mg 12 hourly and verapamil 80 mg 8 hourly. Nifedipine treatment reduced mean total theophylline clearance by 9%, due to decreased clearances via 1-and 3-demethylation. Verapamil treatment reduced mean total theophylline clearance by 14%, due to decreased clearances via 1-and 3-demethylation and 8-hydroxylation. Verapamil and nifedipine at usual clinical doses are unlikely to cause clinically significant changes in theophylline disposition.

“…This is not the case for CBZ as the fraction of the dose metabolized through the epoxide-diol pathway ranges from 0.2 to 0.6 in patients (Bertilsson & Tomson, 1986). In spite of this, CBZ-E/CBZ (Brodie et al, 1983;Macphee et al, 1986;Patel et al, 1981) and CBZ-T/CBZ ratios (Bourgeois & Wad, 1984b) are considered to be sensitive indicators of enzyme induction or inhibition.…”

Section: Discussionmentioning

confidence: 99%

The effect of clobazam on steady state plasma concentrations of carbamazepine and its metabolites.

Muñoz

Salamanca

Diaz-Obregón

et al. 1990

Steady state metabolite/parent drug plasma ratios were measured in 15 epileptic patients on carbamazepine (CBZ) monotherapy and in seven patients treated with CBZ and clobazam (CLB). CBZ plasma concentrations did not differ between the two groups but patients also treated with CLB exhibited higher concentrations of CBZ-10,11-epoxide (CBZ-E) and trans-10,11-dihydro-10,11-dihydroxy-CBZ (CBZ-T). Ratios between all of the metabolites of CBZ and the parent compound were higher in patients on polytherapy but the ratio between metabolites was not different. CLB comedication causes a moderate increase (about 1.5-fold) in CBZ metabolism, probably by inducing its epoxidation.