Stereoselective central nervous system effects of the R- and S-isomers of the GABA uptake blocker N-(4, 4-di-(3-methylthien-2-yl)but-3-enyl) nipecotic acid in the rat.

1. The 'effect compartment' model was applied to characterize the pharmacodynamics of the R- and S-isomers of tiagabine in conscious rats in vivo using increase in the beta activity of the EEG as a pharmacodynamic endpoint. 2. No pharmacokinetic differences in plasma were observed between R- and S-tiagabine. The values for clearance and volume of distribution at steady-state were 103+/-10 versus 90+/-6 ml min(-1) kg(-1) and 1.8+/-0.2 versus 1.6+/-0.2 l kg(-1) for the R- and S-isomer, respectively. In contrast, plasma protein binding showed a statistically significant difference with values of the free fraction of 5.7+/-0.5 and 11.4+/-0.6%. In addition the rate constant for transport to the effect compartment was also different with values of 0.027 versus 0.067 min(-1). 3. For both isomers the relationship between concentration and EEG effect was non-linear and successfully characterized on basis of the Hill equation. A statistically significant difference in the value of EC(50) of 328+/-11 versus 604+/-18 ng ml(-1) was observed for R- and S-tiagabine respectively. The values of the other pharmacodynamic parameters were identical. 4. It is concluded that the differences in in vivo pharmacodynamics of R- and S-tiagabine can be explained by stereoselective differences in both the affinity to the GABA-uptake transporter and the degree of non-specific protein binding in plasma and at the effect site.