Effect of genetic polymorphisms on the transport of anti-seizure medications in hCMEC/D3 cell lines.

[UNLABELLED] The ATP-binding cassette, subfamily G, member 2 (ABCG2) transporter, or breast cancer resistance protein (BCRP), plays a crucial role in the absorption and distribution of various compounds, including anti-seizure medications (ASMs). genetic polymorphisms have been shown to affect the pharmacokinetics of several drugs, including anti-cancer drugs and statins. Clinical studies suggested an association between the variations and ASMs pharmacokinetics. Thus, the aim of the present study was to evaluate the effect of the coding variants, 742T > G and 886G > C on the ABCG2-mediated transport of ASMs, carbamazepine and N-desmethyl clobazam by employing cell-based bidirectional transport experiments. Human cerebral microvascular endothelial cells (hCMEC/D3) were transfected with , carrying either the wild-type allele (742T, 886G) or its mutated counterparts (742G or 886 C). The cells overexpressing variants exhibited significant reduction in mRNA and protein expression levels compared to those with wild-type protein (742T, 886G). This suggests that variants lead to a downregulation in ABCG2 expression. ABCG2 wild-type protein (742T, 886G) actively transported DCLB, with an efflux ratio > 2 that significantly decreased upon addition of ABCG2-specific inhibitor Ko143, confirming its role in DCLB transport. In contrast, CBZ showed an efflux ratio < 1.5 with no notable reduction upon ABCG2 inhibition. 742T > G or 886G > C variants markedly reduced the efflux ratio of DCLB to 1, compared to wild-type protein. In contrast, these variants did not affect CBZ transport. These findings indicate that the genetic polymorphisms studied may account for variability in individual ASM responses, supporting more personalized therapy for epilepsy patients.

[SUPPLEMENTARY INFORMATION] The online version contains supplementary material available at 10.1007/s10616-026-00909-9.