Frigerio E, Benecchi A, Brianceschi G, Pellizzoni C, Poggesi I, Strolin Benedetti M, Dostert P
Pharmacokinetics and Metabolism Department, Pharmacia & Upjohn, Milan, Italy.
Chirality. 1997;9(3):303-6. doi: 10.1002/(SICI)1520-636X(1997)9:3<303::AID-CHIR17>3.0.CO;2-R.
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. The pharmacokinetics of reboxetine enantiomers were determined in a crossover study in three male beagle dogs. Each animal received the following oral treatments, separated by 1-week 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 monitored 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 tmax was about 1 h for both enantiomers. Cmax and AUC were about 1.5 times higher for the (R,R)- than for the (S,S)-enantiomer, mean values +/- SD being 704 +/- 330 and 427 +/- 175 ng/ml for Cmax and 2,876 +/- 1,354 and 1,998 +/- 848 ng.h/ml for AUC, respectively. No differences between the (R,R)- and (S,S)-enantiomers were observed in t1/2 (3.9 h). Total 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 in the main plasma pharmacokinetic parameters were found for either enantiomer on administration of the single enantiomers or reboxetine. No chiral inversion was observed after administration of the separate enantiomers, as already observed in humans.
瑞波西汀，(RS)-2-[(RS)-α-(2-乙氧基苯氧基)苄基]吗啉甲磺酸盐，是一种外消旋化合物，由(R,R)-和(S,S)-对映体的混合物组成。在一项交叉研究中，测定了三只雄性比格犬体内瑞波西汀对映体的药代动力学。每只动物接受以下口服治疗，间隔1周洗脱期：10mg/kg瑞波西汀、5mg/kg(R,R)-和5mg/kg(S,S)-。使用具有荧光检测的对映体特异性高效液相色谱法（定量限：血浆中每种对映体为1.1ng/ml，尿液中为5ng/ml）监测给药后48小时内瑞波西汀对映体的血浆和尿液水平。给予瑞波西汀后，两种对映体的平均达峰时间约为1小时。(R,R)-对映体的Cmax和AUC分别比(S,S)-对映体高约1.5倍，Cmax的平均值±标准差分别为704±330和427±175ng/ml，AUC分别为2876±1354和1998±848ng·h/ml。在半衰期（3.9小时）方面，未观察到(R,R)-和(S,S)-对映体之间存在差异。两种对映体在尿液中的总回收率相似，(R,R)-和(S,S)-对映体的Ae（0 - 48小时）分别为对映体剂量的1.3±0.7%和1.1±0.7%。给予单一异构体或瑞波西汀后，两种对映体的主要血浆药代动力学参数均未发现明显差异。给予单独的对映体后未观察到手性转化，这与在人体中观察到的情况一致。
