title: Stereoselective and species-dependent kinetics of reboxetine in mouse and rat.
abstract: 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.
authors.affiliation: Department of Pharmacokinetics and Metabolism, Pharmacia, Milan, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Strolin Benedetti
authors.forename: E
authors.initials: E
authors.lastname: Frigerio
authors.forename: P
authors.initials: P
authors.lastname: Tocchetti
authors.forename: G
authors.initials: G
authors.lastname: Brianceschi
authors.forename: M G
authors.initials: MG
authors.lastname: Castelli
authors.forename: C
authors.initials: C
authors.lastname: Pellizzoni
authors.forename: P
authors.initials: P
authors.lastname: Dostert
mesh_terms: 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
chemical_list: D000928:Antidepressive Agents; D009025:Morpholines; D000077593:Reboxetine