Potential role for human P‐glycoprotein in the transport of lacosamide

Summary Purpose Antiepileptic drugs ( AED s) do not effectively treat 30–40% of patients with epilepsy. Export of AED s by P ‐glycoprotein ( P gp, ABCB1 , or MDR1 ), which is overexpressed in the blood–brain barrier in drug‐resistant patients, may be a mechanism for resistance to AED s. For most recently approved AED s, whether they are transported by P gp is unknown. We investigated whether a new AED , lacosamide ( LCM ), is a substrate of human P gp. Methods LLC ‐ PK 1 and MDCKII cells transfected with the human MDR 1 gene were used to determine the substrate status of LCM in concentration equilibrium transport assays ( CETAs ). An equal concentration of drug was initially loaded in both the apical and basal chambers, and the concentration in both chambers was measured up to 4 h. The experiments were repeated in the presence of the P gp inhibitors verapamil and tariquidar. Caco‐2 assays were used to determine the intrinsic permeability and efflux ratio of LCM as well as its potential to inhibit digoxin, a P gp substrate. Key Findings Lacosamide was transported by MDR1 ‐transfected cells from basolateral to apical sides. The efflux of LCM could be completely blocked by verapamil or tariquidar. In C aco‐2 assays, LCM showed high permeability without a significant efflux ratio; it did not inhibit digoxin, a P gp substrate. Significance Although LCM is a substrate of P gp in CETA , C aco‐2 data demonstrated that passive diffusion should play a major role in the overall disposition of LCM . The critical role of P gp should be addressed in vivo.