洛索洛芬钠是具有两个手性中心的手性药物。在我们之前的工作中,我们发现消除其四种异构体在大鼠中显示出立体特异性,而立体特异性行为在体内如何发生尚不清楚。为了澄清这个问题,通过手性半制备高效液相色谱(HPLC)制备洛索洛芬钠的每种单一异构体,然后对大鼠给药。通过使用分析型手性HPLC分析大鼠血浆中的每种异构体,发现手性反转仅发生在其(2R)-异构体上,一个来自(1\'S,2R)-至(1\'S,2S)-异构体和另一种来自(1'R,2R)-至(1\'R,2S)-异构体。α-取代的环戊酮的还原仅发生在其(1'R)异构体上,与(1\'R,2R)-异构体还原成(2'S,1\'R,2R)-反式醇和(1'R,2S)-至(2\'S,1\'R,2S)-反式醇。有趣的是,反转和还原反应都发生在其(1\'R,2R)-异构体由于具有(2R)-和(1'R)-构型的特殊立体结构,反过来,他们都没有想到它的(1,2S)-异构体,导致体内消除率显著不同。这些新发现对于评价手性药物的安全性和有效性具有重要意义。
Loxoprofen sodium is a chiral drug with two chiral centers. In our previous work, we found that the elimination of its four isomers showed stereospecificity in rats, while how the stereospecific behavior occurred in vivo was unclear. To clarify this issue, each single isomer of loxoprofen sodium was prepared by a chiral semi-preparative high-performance liquid chromatography (HPLC) and then administered to rats. By analysis of each isomer in rat plasma utilizing an analytical chiral HPLC, it was discovered that the chiral inversion occurred only to its (2R)-isomers, one from (1\'S,2R)- to (1\'S,2S)-isomer and the other from (1\'R,2R)- to (1\'R,2S)-isomer. The reduction of α-substituted cyclopentanone occurred only to its (1\'R)-isomers, with (1\'R,2R)-isomer reduced to (2\'S,1\'R,2R)-trans-alcohol and (1\'R,2S)- to (2\'S,1\'R,2S)-trans-alcohol. Interestingly, both the inversion and the reduction reaction occurred to its (1\'R,2R)-isomer due to the special stereo-structure with both (2R)- and (1\'R)-configuration, and conversely, neither of them occurred to its (1\'S,2S)-isomer, which caused the significantly different elimination rate in vivo. These new findings were meaningful for evaluation of the safety and efficacy of chiral drugs.