CLOFIBRIC ACID INCREASES THE UNIDIRECTIONAL CHIRAL INVERSION OF IBUPROFEN IN RAT-LIVER PREPARATIONS

1. The formation of (S)-ibuprofen from (R)-ibuprofen was monitored in perfused rat livers and in rat hepatocytes and the rate constants calc ulated. 2. Pre-treatment of animals for three days with clofibric acid markedly increased the (R)-to-(S) inversion of ibuprofen in both prep arations. In contrast, clofibric acid did not elicit such a reaction w ith flurbiprofen, an analogue that does nor undergo inversion under co ntrol conditions. 3. An increase in the chiral inversion was also seen when clofibric acid was added to the perfusion medium or to hepatocyt e suspensions. In the latter system this increase was shown to be conc entration dependent. 4. Pre-treatment of rat combined with addition of clofibric acid to the perfusion medium produced a cumulative stimulat ion of (R)-to-(S) inversion of ibuprofen. 5. Clofibric acid added to h epatocyte suspensions transiently increased intracellular concentratio ns of coenzyme A whereas (R)-ibuprofen transiently decreased CoA conce ntrations. The two effects cancelled each other upon co-incubation of the two compounds. 6. It is postulated that the metabolic interaction observed between clofibric acid and (R)-ibuprofen may be due to change s in intracellular concentrations of CoA.