Interactions between SSR504734, a selective glycine transporter type 1 inhibitor, and antiseizure drugs: pharmacodynamic and pharmacokinetic studies in mice.

Studies suggest the potential involvement of glycine in seizures and epilepsy; however, no currently available antiseizure medications directly target glycine transporter 1 (GlyT1) or enhance glycinergic neurotransmission. Here, we examined the effect of SSR504734, a selective GlyT1 inhibitor, on the protective activity of six antiseizure medications, i.e., lamotrigine and topiramate in the maximal electroshock (MES) seizure test; levetiracetam and carbamazepine in the 6 Hz (32 mA) test; and valproate and ethosuximide in the subcutaneous pentylenetetrazole (scPTZ) test in mice. To evaluate potential pharmacokinetic contributions, plasma and brain concentrations of antiseizure drugs and SSR504734 were measured. In addition, the influence of SSR504734 on recombinant human cytochrome P450 isozymes was assessed. The acute adverse-effect profiles of SSR504734 in combination with the studied drugs were also evaluated. SSR504734 significantly potentiated the antiseizure efficacy of almost all tested antiseizure drugs, with the exception of ethosuximide. The interaction between SSR504734 and levetiracetam was purely pharmacodynamic in nature, as no changes in serum or brain drug concentrations were observed. The enhanced antiseizure activity of topiramate, lamotrigine, and carbamazepine could be partially attributed to pharmacokinetic interactions with SSR504734. At higher doses, SSR504734 administered alone or in combination with antiseizure drugs, induced motor impairments and cognitive deficits. Altogether, these in vivo findings indicate that GlyT1 inhibition may complement the mechanisms of action of diverse antiseizure drugs. Further studies are warranted to evaluate the therapeutic potential of GlyT1 inhibitors, preferably those with improved safety profiles, used alone or as adjunctive therapy with antiseizure medications.