Stereoselective and species-dependent kinetics of reboxetine in mouse and rat.
Reboxetine, (RS)-2-[(RS)-alpha-(2-ethoxyphenoxy)benzyl]morpholine methanesulphonate, 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 both enantiomers were determined in mice and rats after oral administration of reboxetine at doses (1.1 mg/kg, mouse; 20 mg/kg, rat) twice the respective ED50 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)-enantiomer. After normalization for dose, the mean AUC0-tz values of both the (R,R)- and (S,S)-enantiomers in mouse brain were about 23 and 32 times higher than in rat brain, respectively. In plasma, the corrected mean AUC0-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 bioavailability and/or lower clearance of both enantiomers in mice than in rats, and for a higher penetration of both enantiomers into mouse brain compared to rat brain.
Strolin Benedetti
M
M
Department of Pharmacokinetics and Metabolism, Pharmacia, Milan, Italy.
Frigerio
E
E
Tocchetti
P
P
Brianceschi
G
G
Castelli
M G
MG
Pellizzoni
C
C
Dostert
P
P
D000818:Animals; D000928:Antidepressive Agents / Q000097:blood / Q000493:pharmacokinetics*; D001682:Biological Availability; D001921:Brain / Q000378:metabolism; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009025:Morpholines / Q000097:blood / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077593:Reboxetine; D013045:Species Specificity; D013237:Stereoisomerism
D000928:Antidepressive Agents; D009025:Morpholines; D000077593:Reboxetine