Stereoselective and species-dependent kinetics of reboxetine in mouse and rat
Stereoselective and species-dependent kinetics of reboxetine in mouse and rat
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DOI：
10.1002/chir.530070416
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发表时间：
1995-01-01
期刊：
影响因子：
2
通讯作者：
Dostert, P
中科院分区：
文献类型：
--
作者：
Benedetti, MS;Frigerio, E;Dostert, P
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）-对映异构体的混合物组成。在本研究中，小鼠和大鼠经口给予瑞波西汀（1.1 mg/kg，小鼠; 20 mg/kg，大鼠）后，测定了两种对映体的脑和血浆水平，剂量为抗利血平试验中相应艾德（50）值的两倍。在用手性试剂（FLEC）衍生化后，使用HPLC法和荧光检测法测定给药后6 h内各对映异构体的血浆和脑浓度。在小鼠和大鼠中，（R，R）-对映异构体的脑和血浆水平始终高于（S，S）-对映异构体。剂量归一化后，小鼠脑中（R，R）-和（S，S）-对映异构体的平均AUC（0-tz）值分别约为大鼠脑中的23倍和32倍。在血浆中，小鼠的校正平均AUC（0-tz）值约为大鼠的5倍（R，R）和10倍（S，S）。这些结果提供了两种对映异构体在小鼠中的生物利用度高于大鼠和/或清除率低于大鼠的证据，以及两种对映异构体在小鼠脑中的渗透性高于大鼠脑的证据。(C)1995 Wiley-Liss，Inc.
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 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)-enantiomer. After normalization for dose, the mean AUC(0-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 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 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. (C) 1995 Wiley-Liss, Inc.