The effects of ibuprofen enantiomers on hepatocyte intermediary metabolism and mitochondrial respiration

In vivo and in vitro (-)R-ibuprofen is inverted to the (+)S antipode via stereoselective formation of an R-ibuprofenyl-CoA intermediate. In this study the effects of (-)R- and (+)S-ibuprofen on metabolism and respiration were studied using isolated rat hepatocytes and mitochondria. R-Ibuprofen significantly increased the lactate to pyruvate ratio, perturbed mitochondrial ketogenesis as evidenced by alterations in the β-hydroxybutyrate to acetoacetate ratio and uncoupled mitochondrial oxidative phosphorylation. In addition, substantial dose- and time-dependent sequestration of reduced CoA (CoASH) occurred in the presence of the R enantiomer. Similarly, S-ibuprofen altered both the cytosolic and mitochondrial redox states although the magnitude of the effect was substantially less than that observed with the R enantiomer. In contrast to R-ibuprofen, S-ibuprofen did not uncouple oxidative phosphorylation or sequester hepatocyte CoASH. It is proposed that the perturbations observed in hepatocyte intermediary metabolism and mitochondrial function are attributable to a combination of the direct effects of R-ibuprofen per se and the sequestration of CoASH as R-ibuprofenyl-CoA during the process of chiral inversion. On the basis of these results, R-ibuprofen should be considered more in terms of metabolism to a reactive acyl-CoA intermediate rather than as a pro-drug for the pharmacologically active S-enantiomer.