STEREOSELECTIVE METABOLIC PATHWAYS OF KETOPROFEN IN THE RAT - INCORPORATION INTO TRIACYLGLYCEROLS AND ENANTIOMERIC INVERSION

The enantiomeric bioinversion of ketoprofen (KP) enantiomers and their incorporation into triacylglycerols were investigated in the rat (1) in vitro, using liver homogenates, subcellular fractions, and hepatocy tes, and (2) in vivo, in different tissue samples after oral administr ation of the radiolabelled compounds. In liver homogenates or subcellu lar fractions, the enantiomer (S)-ketoprofen (S-KP) was recovered unch anged, whereas (R)-ketoprofen (R-KP) was partially converted into its Coenzyme A (CoA) thioester and inverted to S-KP. Both processes occurr ed mainly in the mitochondrial fraction. This supports the mechanism o f inversion via stereoselective formation of CoA thioesters of R-KP, a lready described for other non-steroidal anti-inflammatory drugs. Inco rporation into triacylglycerols was detected after incubation with int act hepatocytes in the presence of added glycerol. The process was ste reoselective for R-KP vs. S-KP (covalently bound radioactivity 26,742 +/- 4,665 dpm/10(6) cells vs. 6,644 +/- 3,179 dpm/10(6) cells, respect ively). However, no incorporation was found in liver samples after ora l administration of either R-KP or S-KP. On the contrary, in adipose t issue samples a significant and stereoselective formation of hybrid tr iacylglycerols was observed: 11,076 +/- 2,790 dpm.g(-1) for R-KP vs. 6 60 +/- 268 dpm.g(-1) for S-KP. The incorporated R/S ratio, higher in a dipose tissue (R/S = 17) than in hepatocytes (R/S = 4), indicates that fat may be the main tissue store for the xenobiotic R-KP in rats. (C) 1996 Wiley-Liss, Inc.