STEREOSELECTIVE AND SPECIES-DEPENDENT KINETICS OF REBOXETINE IN MOUSEAND RAT

Reboxetine, )-2-[(RS)-alpha-(2-ethoxyphenoxy)benzyl]morpholine methane sulphonate, is a racemic compound and consists of a mixture of the (R, R)- and (S,S)-enantiomers. In this study, brain and plasma levels of b oth enantiomers were determined in mice and rats after oral administra tion of reboxetine at doses (1.1 mg/kg, mouse; 20 mg/kg, rat) twice th e respective ED(50) values in the antireserpine test. Plasma and brain concentrations of each enantiomer were measured up to 6 h postdosing using an HPLC method with fluorimetric detection after derivatization with a chiral agent (FLEC). In mice and rats, brain and plasma levels of the (R,R)-enantiomer were always higher than those of the (S,S)-ena ntiomer. After normalization for dose, the mean AUC(0-tz) values of bo th the (R,R)- and (S,S)-enantiomers in mouse brain were about 23 and 3 2 times higher than in rat brain, respectively. In plasma, the correct ed mean AUC(0-tz) values were about 5 (R,R) and 10 (S,S) times higher in mice than in rats. These results provide evidence for the higher bi oavailability and/or lower clearance of both enantiomers in mice than in rats, and for a higher penetration of both enantiomers into mouse b rain compared to rat brain. (C) 1995 Wiley-Liss, Inc.