THE SIMULTANEOUS ESTIMATION OF THE INFLUX AND EFFLUX BLOOD-BRAIN-BARRIER PERMEABILITIES OF GABAPENTIN USING A MICRODIALYSIS-PHARMACOKINETICAPPROACH

Purpose. To determine the apparent bidirectional permeabilities of gab apentin (GBP) across the blood-brain barrier (BBB) using a novel micro dialysis-pharmacokinetic approach. Methods. Rats were administered int ravenous infusions of [C-14]GBP to achieve clinically relevant steady- state plasma concentrations. Microdialysis was used to monitor GBP con centration in brain extracellular fluid (ECF) in conscious animals. Br ain tissue GBP concentration was measured at termination. The BBB infl ux (CL(1)) and efflux (CL(2)) permeabilities of GBP were estimated wit h 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 i ndependently 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 t issue concentrations determined after intravenous bolus administration and validated this pharmacokinetic-microdialysis approach for estimat ion of BBB permeabilities. The values for CL(1) and CL(2) 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 to tal brain tissue concentration of GBP was significantly higher than th e ECF concentration at steady-state due to intracellular accumulation and tissue binding, that if not considered, will lead to underestimate d efflux BBB permeability using the tissue homogenate-pharmacokinetic approach.