摘要：Intestinal chiral inversion of ibuprofen is still lacking direct evidence. In a preliminary experiment, ibuprofen was found to undergo inversion in Caco-2 cells. This investigation was thus conducted to determine the characteristics and influence of some biochemical factors on the chiral inversion of ibuprofen in Caco-2 cells. The effects of substrate concentration (2.5—40 μg/ml), cell density (0.5—2×106 cells/well), content of serum (0—20%), coexistence of S ibuprofen (corresponding doses), sodium azide (10 m M ), exogenous Coenzyme A (CoA) (0.1—0.4 m M ), and palmitic acid (5—25 μ M ) on inversion were examined. A stereoselective HPLC method based on the Chromasil-CHI-TBB column was developed for quantitative analysis of the drug in cell culture medium. The inversion ratio ( F i) and elimination rate constant were calculated as the indexes of inversion extent. Inversion of ibuprofen in Caco-2 cells was found to be both dose and cell density dependent, indicating saturable characteristics. Addition of serum significantly inhibited the inversion, to an extent of 2.7 fold decrease at 20% content. Preexistence of S enantiomer exerted a significant inhibitory effect ( p <0.01 for all tests). Sodium azide decreased the inversion ratio from 0.43 to 0.32 ( p <0.01). Exogenous CoA and palmitic acid significantly promoted the inversion at all tested doses ( p <0.01 for all tests). This research provided strong evidence to the capacity and capability of intestinal chiral inversion. Although long incubation times up to 120 h were required, Caco-2 cells should be a suitable model for chiral inversion research of 2-APAs considering the human-resourced and well-defined characteristics from the present study.
关键词：ibuprofen;presystemic inversion;Caco-2 cell;Coenzyme A (CoA);palmitic acid
