Study of the stereospecificity in the biotransformation of the four isomers of loxoprofen sodium in rats by chiral HPLC

Abstract

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.