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  • 1
    Electronic Resource
    Electronic Resource
    Stereoselective metabolic pathways of ketoprofen in the rat: Incorporation into triacylglycerols and enantiomeric inversion (1996)
    New York, NY [u.a.] : Wiley-Blackwell
    Chirality 8 (1996), S. 163-172 
    Details
    ISSN: 0899-0042
    Keywords: arylpropionic acid ; ketoprofen ; enantiomer ; stereoselectivity ; Coenzyme A thioester ; hybrid triacylglycerols ; inversion ; adipose tissue ; hepatocytes ; Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: 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 hepatocytes, and (2) in vivo, in different tissue samples after oral administration of the radiolabelled compounds. In liver homogenates or subcellular fractions, the enantiomer (S)-ketoprofen (S-KP) was recovered unchanged, whereas (R)-ketoprofen (R-KP) was partially converted into its Coenzyme A (CoA) thioester and inverted to S-KP. Both processes occurred mainly in the mitochondrial fraction. This supports the mechanism of inversion via stereoselective formation of CoA thioesters of R-KP, already described for other non-steroidal anti-inflammatory drugs. Incorporation into triacylglycerols was detected after incubation with intact hepatocytes in the presence of added glycerol. The process was stereoselective for R-KP vs. S-KP (covalently bound radioactivity 26,742 ± 4,665 dpm/106 cells vs. 6,644 ± 3,179 dpm/106 cells, respectively). However, no incorporation was found in liver samples after oral administration of either R-KP or S-KP. On the contrary, in adipose tissue samples a significant and stereoselective formation of hybrid triacylglycerols was observed: 11,076 ± 2,790 dpm.g-1 for R-KP vs. 660 ± 268 dpm.g-1 for S-KP. The incorporated R/S ratio, higher in adipose 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. © 1996 Wiley-Liss, Inc.
    Additional Material: 2 Ill.
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  • 2
    Electronic Resource
    Electronic Resource
    Stereoselective inhibition of rat brain cyclooxygenase by dexketoprofen (1997)
    New York, NY [u.a.] : Wiley-Blackwell
    Chirality 9 (1997), S. 281-285 
    Details
    ISSN: 0899-0042
    Keywords: dexketoprofen ; enantiomer ; stereoselectivity ; brain ; cyclooxygenase ; rat ; Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: Although it has been assumed that the effects of nonsteroidal antiinflammatory drugs (NSAIDs) are mainly the result of their action on local synthesis of prostaglandins, there is growing evidence to suggest that they may also exert a central analgesic action. Some authors have suggested that inhibition of prostaglandin synthesis in the brain could contribute to the analgesic action. The effect of dexketoprofen trometamol (tromethamine salt of the enantiomer (+)-S-ketoprofen) on prostaglandin synthesis was investigated in rat brain fragments and in cyclooxygenase preparations from rat brain microsomes. Effects of the (-)-R-enantiomer and the racemic mixture were also evaluated. Significant levels of prostaglandin F2α (PGF2α) were synthesized in rat brain fragments after 10 min of incubation at 37°C. Dexketoprofen was found to be a potent inhibitor of this PGF2α production in rat brain (IC50 = 6.2 nM), and it completely suppressed PGF2α production at 1 μM concentration. In addition, inhibition of PGF2α synthesis by dexketoprofen was highly stereoselective since the enantiomer (-)-R-ketoprofen was significantly less potent (IC50 = 294 nM); with this enantiomer, even at high concentrations such as 1 μM, less than 60% inhibition was achieved. These results correlated with those obtained in the study of racemic ketoprofen and its enantiomers on cyclooxygenase activity of rat brain microsomes, where dexketoprofen also inhibited enzymatic activity stereoselectively. IC50 values obtained for dexketoprofen, (-)-R-ketoprofen, and rac-ketoprofen were 3.5 μM, 45.3 μM, and 5.8 μM, respectively. The above results could be related to the potent analgesic effect of dexketoprofen observed in vivo, which was also stereoselective. Taken together, these findings suggest that prostaglandin synthesis inhibition in rat brain by dexketoprofen could be associated, at least in part, with the analgesic effect of this NSAID. Chirality 9:281-285, 1997. © 1997 Wiley-Liss, Inc.
    Additional Material: 3 Ill.
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