Abstract

Deuterium labeling techniques and stereoselective GC/MS methodology have been employed to investigate the mechanism by which R-ibuprofen undergoes metabolic chiral inversion in the rat in vivo. Following oral administration of a mixture of R-ibuprofen (7.5 mg kg-1) and R-[ring-2H4; 2-2H]ibuprofen (R-[2H5]ibuprofen) (7.5 mg kg-1) to male Sprague-Dawley rats, the enantiomeric composition and deuterium excess of the drug were determined in serial plasma samples and in pooled urine collected over 10 hr. The results demonstrate that: (i) R-ibuprofen undergoes extensive inversion of configuration to its S antipode in the rat; (ii) chiral inversion of R-[2H5]ibuprofen yields S-[2H4]ibuprofen in a process that involves quantitative loss of the deuterium atom present originally at C-2; (iii) labeling of R-ibuprofen with deuterium at C-2 does not introduce a measurable kinetic deuterium isotope effect on the chiral inversion reaction; and (iv) metabolism of R-[2H5]ibuprofen leads to the appearance in plasma and urine of molecules of R-ibuprofen labeled with 4 atoms of deuterium. On the basis of these findings, a mechanism is proposed for the chiral inversion reaction that invokes the stereoselective formation of the coenzyme A thioester of R-ibuprofen as a key metabolite; conversion of this species to the corresponding enolate tautomer affords a symmetrical intermediate through which racemization of ibuprofen occurs in vivo.