Optical inversion of (2R)- to (2S)-isomers of 2-(4-(2-oxocyclopentylmethyl)-phenyl)propionic acid (loxoprofen), a new anti-inflammatory agent, and its monohydroxy metabolites in the rat.

Abstract

Enantiomer ratios of 2-[4-(2-oxocyclopentylmethyl)phenyl]propionic acid (loxoprofen) and its monohydroxy metabolites in plasma of rats were determined by high performance liquid chromatography (HPLC) after derivatization with the chiral reagent, (1S)-1-(4-dimethylaminonaphthalen-1-yl)ethylamine. The ratios of (2S)- to (2R)-isomers of the parent acid and 2-[4-(trans-2-hydroxycyclopentylmethyl)phenyl]propionic acid (trans-alcohol) increased rapidly with time after oral administration of racemic and (2R)-loxoprofen, while the (2S)-configuration remained completely intact after dosing with (2S)-isomer. Irreversible optical inversion of (2R)- to (2S)-loxoprofen evidently occurred in rats. The administration of trans- and cis-alcohols showed that the optical inversion also occurs in these monohydroxy metabolites and the cis-alcohol is easily converted to the trans-alcohol through the parent acid, but the latter is not converted to the former.