The Metabolism of Ibuprofen by the Rat Liver
Crimmins, Curtis A.
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In situ rat liver perfusion techniques were used to examine the metabolism of ibuprofen by the rat liver. Ibuprofen is a non-steroidal anti-inflammatory agent that is clinically administered as a racemic mixture. It. is metabolized by the oxidation of the isobutyl side chain and by the chiral inversion of the methinyl carbon of the propionic acid group. Results indicated that the inversion is stereoselective, proceeding from R to S configuration and not vice versa. In this study, normal healthy livers were compared to fatty diseased livers that had undergone diet-induced cirrhosis. Results showed that the total hepatic clearance of the R isomer was higher in the control livers than in the fatty livers. However, this decrease in R clearance between the control and fatty livers was not seen as a reduction of the clearance due to inversion, but as a reduction in the clearance due to mechanisms other than chiral inversion. Thus, although a decrease in the ability to metabolize ibuprofen was observed in the fatty livers, the chiral inversion pathway was apparently unaffected by liver disease. This is a significant finding, since the pharmacological activity of ibuprofen has been found to lie almost exclusively in the S isomer. A reduction of the ability to catalyze the R to the S isomer would greatly diminish the drug's potency. Since ibuprofen is administered as a racemic mixture, the chiral inversion pathway is very important to the metabolism of the drug.