Metabolic inversion of (R)-ibuprofen. Epimerization and hydrolysis of ibuprofenyl-coenzyme A

Abstract

Ibuprofen [(racemic)2-(4-isobutylphenyl)propionic acid] has been proposed but not directly demonstrated to undergo unidirectional inversion from the (R)- to the (S)-configuration via a coenzyme A (CoA) thioester intermediate. Chemically synthesized (R)- and (S)-ibuprofenyl-CoA, and rat and human liver homogenates were used to investigate the relative rates of ibuprofenyl-CoA epimerization and hydrolysis. Rat whole liver homogenate completely epimerized (R)- or (S)-ibuprofenyl-CoA, whereas hydrolysis of this intermediate occurred at a much slower rate. Rat liver mitochondria was the most efficient at both epimerizing and hydrolyzing ibuprofenyl-CoA, whereas rat liver microsomes hydrolyzed ibuprofenyl-CoA at a rate similar to whole liver homogenate but had very little epimerization activity. Rat liver cytosol was the poorest at hydrolyzing ibuprofenyl-CoA but had substantial epimerization capability. Whole liver homogenate from human tissue was less efficient at epimerizing but as efficient at hydrolyzing ibuprofenyl-CoA as rat whole liver homogenate. No stereoselectivity of either epimerization or hydrolysis was noted for any of the enzyme preparations studied. This study demonstrates that the inversion of (R)-ibuprofen occurs, at least in part, via the epimerization of the metabolic intermediate, ibuprofenyl-CoA, in both rat and human liver tissues.