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