Organic anion transporting polypeptide 2 transports valproic acid in rat brain microvascular endothelial cells

Objectives: Abnormal drug transporter expression or function in the brain may lead to decreased concentrations of antiepileptic drugs (AEDs) in the central nervous system in patients with drug-resistant epilepsy. We previously showed the influx transporter organic anion transport polypeptide 2 (Oatp2) was expressed in rat brain microvascular endothelial cells (BMECs). Seizures decrease expression of Oatp2, but it remains unclear whether Oatp2 transports AEDs. In this study, we utilized rat BMECs as an in vitro model of the blood-brain barrier (BBB) to study Oatp2-mediated transport of valproic acid (VPA), the most common clinically used AEDs.Methods:In vivo injection of pregnenolone-16-carbonitrile was used to induce high expression of Oatp2 in isolated BMECs. Small interfering RNA treatment was used to silence Oatp2, and uptake of VPA was assessed.Results: Increased expression of Oatp2 in BMECs increased the uptake of VPA, while inhibition of Oatp2 reduced VPA uptake.Discussion: This study indicates Oatp2 transports VPA across the BBB, and suggests altered Oatp2 expression may contribute to resistance to VPA in patients with drug-resistant epilepsy.