PHARMACOKINETICS OF REBOXETINE ENANTIOMERS IN THE DOG

Reboxetine, (RS) 2-[(RS)-alpha-(2-ethoxyphenoxy)benzyl] morpholine met hanesulphonate, is a racemic compound and consists of a mixture of the (R,R)- and (S,S)-enantiomers. The pharmacokinetics of reboxetine enan tiomers were determined in a crossover study in three male beagle dogs . Each animal received the following oral treatments, separated by 1-w eek washout period: 10 mg/kg reboxetine, 5 mg/kg (R,R)and 5 mg/kg (S,S )-. Plasma and urinary levels of the reboxetine enantiomers were monit ored up to 48 h post-dosing using an enantiospecific HPLC method with fluorimetric detection (LOQ: 1.1 ng/ml in plasma and 5 ng/ml in urine for each enantiomer). After reboxetine administration mean t(max) was about 1 h for both enantiomers. C-max and AUC were about 1.5 times hig her for the (R,R)- than for the (S,S)-enantiomer, mean values +/- SD b eing 704 +/- 330 and 427 +/- 175 ng/ml for C-max and 2,876 +/- 1,354 a nd 1,998 +/- 848 ng.h/ml for AUG, respectively, No differences between the (R,R)- and (S,S)-enantiomers were observed in t(1/2) (3.9 h). Tot al recovery of the two enantiomers in urine was similar, the Ae (0-48 h) being 1.3 +/- 0.7 and 1.1 +/- 0.7% of the enantiomer dose for the ( R,R)- and the (S,S)-enantiomers, respectively. No marked differences i n the main plasma pharmacokinetic parameters were found for either ena ntiomer on administration of the single enantiomers or reboxetine. No chiral inversion was observed after administration of the separate ena ntiomers, as already observed in humans. Chirality 9:303-306, 1997. (C ) 1997 Wiley-Liss, Inc.