Saturable transport of gabapentin at the blood-brain barrier

Gabapentin readily crosses the blood-brain barrier and concentrates in brai n tissue via an active transport process believed to be system-L. Blood-bra in barrier system-L has a low K-m, making it particularly susceptible to su bstrate saturation. The purpose of this study was to determine whether the fraction of gabapentin crossing the blood-brain barrier remains constant ov er a broad range of doses. Using a rat model, microdialysis techniques were employed to determine if fluctuations in gabapentin concentrations in the brain extracellular fluid (ECF) coincided with proportional changes in plas ma concentrations. Area under the concentration-time curve was,as calculate d for plasma (AUC(plasma)) and brain extracellular fluid (AUC(ECF)) The rat ios of AUF(ECF) to AUC(plasma) (AUC(ratio)) and brain extracellular fluid t o midpoint plasma gabapentin concentration for each collection interval (C- ratio) were determined to provide indicators of the relative (i.e. fraction al) amount of gabapentin crossing the blood-brain barrier. Analysis of the association between AUC(ECF) and AUC(plasma) using linear regression analys is revealed a small, but significant relationship (r = 0.62; p < 0.01). Alt hough higher AUC(ECF) values were obtained with higher AUC(plasma) values, changes in AUC(ECF) were less than proportional to observed changes in AUC( plasma). Blood-brain barrier saturation of gabapentin transport was evident as the AUC(ratio) decreased with increased AUC(plasma). Collectively, thes e results support a trend towards saturation at higher plasma concentration s of the carrier-mediated transport mechanism of gabapentin through the blo od-brain barrier.