Interactions between modulators of the GABAA receptor: Stiripentol and benzodiazepines

Abstract

Many patients with refractory epilepsy are treated with polytherapy, and nearly 15% of epilepsy patients receive two or more anti-convulsant agents. The anti-convulsant stiripentol is used as an add-on treatment for the childhood epilepsy syndrome known as severe myoclonic epilepsy in infancy (Dravet Syndrome). Stiripentol has multiple mechanisms of action, both enhancing GABAA receptors and reducing activity of metabolic enzymes that break down other drugs. Stiripentol is typically co-administered with other anti-convulsants such as benzodiazepines which also act through GABAA receptor modulation. Stiripentol slows the metabolism of some of these drugs through inhibition of a variety of cytochrome P450 enzymes, but could also influence their effects on GABAergic neurotransmission. Is it rational to co-administer drugs which can act through the same target? To examine the potential interaction between these modulators, we transiently transfected HEK-293T cells to produce α3β3γ2L or α3β3δ recombinant GABAA receptors. Using whole-cell patch clamp recordings, we measured the response to each benzodiazepine alone and in combination with a maximally effective concentration of stiripentol. We compared the responses to four different benzodiazepines: diazepam, clonazepam, clobazam and norclobazam. In all cases we found that these modulators were equally effective in the presence and absence of stiripentol. The δ-containing receptors were insensitive to modulation by the benzodiazepines, which did not affect potentiation by stiripentol. These data suggest that stiripentol and the benzodiazepines act independently at GABAA receptors and that polytherapy could be expected to increase the maximum effect beyond either drug alone, even without consideration of changes in metabolism.

Audit of use of stiripentol in adults with Dravet syndrome

“…A rodent model of established status epilepticus showed effectiveness of stiripentol when seizures had already become resistant to treatment with benzodiazepines, by potentiating GABAergic inhibition. The action of stiripentol seemed independent of the benzodiazepine binding site on the GABAA receptor 27, 28, 29, 30…”

“…Stiripentol has an inhibitory effect on clobazam metabolism, mostly mediated by CYP3A4 and CYP2C19, leading to increased plasma concentrations of both clobazam and its active metabolite, norclobazam (desmethylclobazam) 17, 31, 32. This pharmacokinetic drug interaction, along with the fact that stiripentol and clobazam/norclobazam act through separate sites on the GABAA receptor,27, 28, 29, 30 may contribute to the effectiveness as well as the adverse effects of stiripentol. Conversely, data collected in two independent multicentre randomized, double‐blind, placebo‐controlled trials in DS patients, STICLO‐France and STICLO‐Italy,17, 32 did not show any significant interaction between stiripentol and sodium valproate.…”

GABAA Receptor Physiology and Its Relationship to the Mechanism of Action of the 1,5-Benzodiazepine Clobazam

“…Clobazam and N-CLB were also effective at the a 3 b 3 g 2 L receptor, with potencies similar to one another, but lower than that of diazepam. [80] Despite the lower potency of clobazam, its maximum efficacy was similar to diazepam. N-CLB, on the other hand, had a maximum efficacy roughly half that of clobazam, reflective of the lower in vivo activity and partial agonism of N-CLB.…”

“…[52] Table III summarizes key GABA A receptor subtypes and associated characteristics. [52][53][54][55][73][74][75][76][77][78][79][80][81] …”

“…[85] In a recent in vitro investigation, human HEK-293T cells were transfected to create recombinant GABA A receptors, as well as recombinant a 3 b 3 g 2 L and a 3 b 3 d GABA A receptors. [80] Cells were evaluated with benzodiazepines diazepam, clonazepam, clobazam and N-CLB in the presence or absence of the anticonvulsant stiripentol. The d-containing receptors were insensitive to any of the benzodiazepines, but were potentiated by stiripentol.…”