Brain microdialysis and PK/PD correlation of pregabalin in rats

Pregabalin [PGB, (S)-3-isobutyl GABA, CI-1008] is a derivative of the inhib itory neurotransmitter g-aminobutyric acid (GABA). It has shown anticonvuls ant, analgesia and anxiety activity in animal models. In this report, blood -brain barrier (BBB) influx and efflux of PGB were investigated with microd ialysis at efficacious doses in rats.' BBB influx (CLin) and efflux (CLout) permeability for pregabalin were 4.8 a nd 37.2 muL/min/g brain, respectively, following an intravenous infusion to rats. The results indicate that PGB is brain penetrable, supporting its an ti-epilepsy and other CNS pharmacology. Significant anticonvulsant action o f PGB was detected between 2 and 8 hr post oral dose, which is lag behind E CF drug concentrations lees. A PK/PD link model was used to describe the co unter-clockwise hysteresis relationship between pregabalin brain ECF concen tration and the anticonvulsant effect in rats. The resulting C-e (concentra tion in effect compartment) versus effect profile exhibits a sigmoidal curv e and the calculated ECe50 and K-eo values were 95.3 ng/mL and 0.0092 min-1 , respectively. The small K-eo value suggests that the effect is not direct ly proportional to the amount of pregabalin in the ECF compartment possibly due to inherent delay.