Study On Cytochrome P450 2C11 Enzyme Activity And Its Application By High Performance Liquid Chromatography

Cytochrome P450(CYP)2C9,as the important phase I drug metabolism enzymes,accounts for about 20%of hepatic total CYP content and metabolizes 15%of current clinical drugs.CYP2C11 in rats highly corresponds with CYP2C9 in humans.In the present work,tolbutamide and warfarin were selected as probe substrates recommended by FDA,to study the activity of CYP2C11 enzyme in vitro and in vivo in rats,using HPLC-DAD/LC-MS/MS.This study explored the effects of herb monomers(cucurbitacin E,celastrol,maslinic acid)and synthesized small molecules(YF479,YR290)on the activity of CYP2C11 in rats for the first time.In in vitro inhibition and kinetic experients,celastrol,YF479 and YR290 competitively inhibited CYP2C11 activity.Cucurbitacin E(CuE)was a moderate and concentration-dependently competitive inhibitor of rat CYP2C11.Maslinic acid did not affect rat CYP2C11.In in vivo experiments,high dose treatment of CuE once or in three consecutive days increased the mean residence time and plasma half-life of tolbutamide with decrease in clearance.Moreover,CuE also inhibited the metabolism of warfarin,as well as strengthened its anticoagulative effects.All these data indicated that CuE affected the metabolism of tolbutamide and warfarin by inhibiting CYP2C11 acitivity in rats.Since there are species difference in CYP expression and activity between human and rat,further studies should be conducted to assess the effects of these compounds on human CYP2C9 enzyme.