The simultaneous estimation of the influx and efflux blood-brain barrier permeabilities of gabapentin using a microdialysis-pharmacokinetic approach.

Purpose: To determine the apparent bidirectional permeabilities of gabapentin (GBP) across the blood-brain barrier (BBB) using a novel microdialysis-pharmacokinetic approach.

Methods: Rats were administered intravenous infusions of [14C]GBP to achieve clinically relevant steady-state plasma concentrations. Microdialysis was used to monitor GBP concentration in brain extracellular fluid (ECF) in conscious animals. Brain tissue GBP concentration was measured at termination. The BBB influx (CL1) and efflux (CL2) permeabilities of GBP were estimated with a hybrid pharmacokinetic model assuming that transport between intra- and extracellular space was more rapid than transport across the BBB. The time course of GBP concentration in brain tissue was determined independently to validate the model assumption.

Results And Conclusions: Simulations of the concentration-time course of GBP in brain tissue based on this modeling correlated well with the time-course of brain tissue concentrations determined after intravenous bolus administration and validated this pharmacokinetic-microdialysis approach for estimation of BBB permeabilities. The values for CL1 and CL2 were 0.042 (0.017) and 0.36 (0.16) ml/min.g-brain, respectively, indicating that GBP was more efficiently transported from brain ECF to plasma. The total brain tissue concentration of GBP was significantly higher than the ECF concentration at steady-state due to intracellular accumulation and tissue binding, that if not considered, will lead to underestimated efflux BBB permeability using the tissue homogenate-pharmacokinetic approach.