Abstract

Ibuprofen [(racemic)2-(4-isobutylphenyl)propionic acid] undergoes metabolic inversion via formation, epimerization, and hydrolysis of the coenzyme A (CoA) thioester, ibuprofenyl-CoA. In this study, (R)-ibuprofen was incubated with either rat whole liver homogenate, human whole liver homogenate, rat liver mitochondria, or rat liver microsomes, and the formation of ibuprofenyl-CoA measured. Rat whole liver homogenate (Vmax/KM = 0.022 +/- 0.005 ml/min/mg protein) was approximately 4-fold more efficient at forming ibuprofenyl-CoA than human whole liver homogenate (Vmax/KM, = 0.005 +/- 0.004 ml/min/mg protein). Rat liver microsomes (Vmax/KM = 0.047 +/- 0.019 ml/min/mg protein) were approximately 2-fold more efficient than rat whole liver homogenate at forming ibuprofenyl-CoA, whereas rat liver mitochondria (Vmax/KM = 0.027 +/- 0.017 ml/min/mg protein) did not differ from whole liver homogenate. Palmitic (Ki = 0.005 mM) and octanoic acids (Ki = 0.19 mM) were capable of inhibiting ibuprofenyl-CoA formation, whereas propionic acid had no effect, suggesting the possible involvement of both long- and medium-chain fatty acyl-CoA synthetases. Of the xenobiotics tested, only bezafibrate (Ki = 0.85 mM) and (S)-ibuprofen (Ki = 0.095 mM in rats, 0.32 mM in human tissue) were capable of substantially inhibiting ibuprofenyl-CoA formation. Thus, it appears that the metabolic inversion of ibuprofen involves lipid-metabolizing pathways and may be affected by fatty acids or xenobiotics.