Inversion of (R)‐ to (S)‐ketoprofen in eight animal species

Åberg, Gunnar; Ciofalo, Vincent B.; Pendleton, Robert G.; Ray, Gene; Weddle, Diann L.

doi:10.1002/chir.530070513

Cited by 59 publications

(35 citation statements)

References 10 publications

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“…Chiral inversion of most NSAIDs proceeds in one direction-usually the R-enantiomer is transformed into the S-enantiomer. 16,27,28 Bidirectional inversion of both enantiomers was observed only sporadically. 29,30 Chiral inversion has been described not only for the 2-arylpropionates (profens), but also for 2-aryloxypropionates (oxyprofen herbicides) 16,31 and D-leucine.…”

Section: Discussionmentioning

confidence: 91%

“…16 As with other enzymatic reactions, the quantitative course of chiral inversion also depends on a number of factors, such as the animal species. 27,39,40 Chiral analysis of residual substrate in the cultivation medium showed that R-(+)-F is converted into its respective antipode in hepatocytes. As a small amount of R-(+)-F was detected in hepatocytes from donor 4 incubated with S-(−)-F, the chiral inversion of S-(−)-F cannot be excluded.…”

Section: Discussionmentioning

confidence: 99%

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Chiral aspects of metabolism of antiinflammatory drug flobufen in human hepatocytes

et al. 2003

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The metabolism of the nonsteroidal antiinflammatory drug flobufen, 4-(2',4'-difluorobiphenyl-4-yl)-2-methyl-4-oxobutanoic acid, was studied in primary cultures of human hepatocytes prepared by two-step collagenase perfusion of livers from four donors. Racemic flobufen or its individual enantiomers, R-(+)- and S-(-)-flobufen were used as substrates. Aliquots of culture medium were collected during 24-h incubation. The time-dependent disappearance of flobufen enantiomers and the formation of metabolites (stereoisomers of dihydroflobufen (DHF)) in hepatocytes were measured by chiral HPLC. The reduction of flobufen in human hepatocytes was stereoselective ((+)-R-flobufen was preferentially metabolized) and stereospecific ((2R;4S)-DHF and (2S;4S)-DHF stereoisomers were mostly formed). Although the structure of flobufen is different from the profens (2-arylpropionates), flobufen undergoes chiral inversion in human hepatocytes. The inversion of R-(+)-flobufen to S-(-)-flobufen predominates. The individual DHF stereoisomers were incubated in hepatocyte cultures and their biotransformation studied. The unidirectional chiral inversion of (2S;4S)-DHF to (2R;4S)-DHF and (2R;4R)-DHF to (2S;4R)-DHF was observed. Stereoselective oxidation of the DHFs to flobufen was also detected. Thus, flobufen metabolism in primary cultures of human hepatocytes is much more complicated (via chiral inversion and DHF re-oxidation) than was presumed from a preliminary achiral point of view.

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Section: Discussionmentioning

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Chiral aspects of metabolism of antiinflammatory drug flobufen in human hepatocytes

et al. 2003

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“…To compare the effects of the pure enantiomers of ketoprofen on prostaglandin release from brain, ex vivo experiments cannot be performed in the rat since a high degree of bioinversion is observed when the (−)-R-enantiomer is administered orally. 13,14,21 Thus, for better comparison we assessed the effects of these compounds when brain portions were incubated in oxygenated Tyrode solution in the presence or absence of compounds at 37°C for 10 min, according to a procedure previously described elsewhere. 8 At this time point, PGF 2␣ production in the absence of inhibitor was significantly different from production at zero time, and inhibition by dexketoprofen was also significant.…”

Section: Stereoselective Inhibition Of Brain Coxmentioning

confidence: 99%

Stereoselective inhibition of rat brain cyclooxygenase by dexketoprofen

Carabaza¹,

Cabré²,

Am³

et al. 1997

Chirality

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“…3 Previous work from our group suggested 80% and 10% chiral inversion for ketoprofen in rats 4 and humans, 5 respectively. Further, Aberg et al 6 found inversion of R-ketoprofen to its antipode in eight species. They classified the studied animals as either ''extensive'' (>50% inversion) or ''limited'' (<50%) inverters depending on their ability to invert R-ketoprofen.…”

Section: Introductionmentioning

confidence: 97%

Bi-directional chiral inversion of ketoprofen in CD-1 mice

1997

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The R enantiomers of some of the 2‐arylpropionic acid non‐steroidal antiinflammatory drugs (NSAIDs) are known to undergo metabolic chiral inversion to their more pharmacologically active antipodes. This process is drug and species dependent and usually unidirectional. The S to R chiral inversion, on the other hand, is rare and has been observed, in substantial extents, only for ibuprofen in guinea pigs and 2‐phenylpropionic acid in dogs. After i.p. administration of single doses of racemic ketoprofen or its optically pure enantiomers to male CD‐1 mice and subsequent study of the concentration time‐course of the enantiomers, we noticed substantial chiral inversion in both directions. Following racemic doses, no stereoselectivity in the plasma‐concentration time courses was observed. After dosing with optically pure enantiomer, the concentration of the administered enantiomer predominated during the absorption phase. During the terminal elimination phase, however, the enantiomers had the same concentrations. Our observation is suggestive of a rapid and reversible chiral inversion for ketoprofen enantiomers in mice. Chirality 9:29–31, 1997. © 1997 Wiley‐Liss, Inc.

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Inversion of (R)‐ to (S)‐ketoprofen in eight animal species

Cited by 59 publications

References 10 publications

Chiral aspects of metabolism of antiinflammatory drug flobufen in human hepatocytes

Chiral aspects of metabolism of antiinflammatory drug flobufen in human hepatocytes

Stereoselective inhibition of rat brain cyclooxygenase by dexketoprofen

Bi-directional chiral inversion of ketoprofen in CD-1 mice

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