L-Type amino acid transporter 1-mediated developmental change of cerebral gabapentin distribution across the rat blood-brain barrier

Gabapentin is an anticonvulsant used in the pharmacotherapy of pediatric epilepsy. Differences in transporter-mediated cerebral drug/compound distribution across the blood-brain barrier (BBB) have been reported between neonates/infants, and adults. The purpose of our study was to comprehensively elucidate the transport of gabapentin across the BBB during childhood and its regulatory molecular systems. The cerebral distribution of [³H]gabapentin in 7-day-old rats was significantly lower than that in 42-day-old adult rats, suggesting weaker gabapentin transport in the BBB of neonates/infants than in adults. In vivo brain uptake and in vitro transport studies have indicated the involvement of transporters that accept large neutral amino acids in the cerebral gabapentin distribution across the BBB. In particular, an in vitro study using RNA interference suggested a major contribution of L-type amino acid transporter 1 (LAT1) to gabapentin transport across the BBB. In the brains of 7-day-old rats, the mRNA expression of LAT1 and the heavy chain of the 4F2 antigens (4F2hc), which forms a complex with LAT1, was reduced compared to that of 42-day-old rats. Consequently, it is suggested that a decrease in gabapentin distribution to the brain across the BBB contributes to the transcriptional reduction of cerebral LAT1 and 4F2hc.