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

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 β activity of the EEG as a pharmacodynamic endpoint. 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. 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 EC50 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. 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. British Journal of Pharmacology (1999) 128, 1651–1658; doi:10.1038/sj.bjp.0702962