Rac‐Flurbiprofen is more ulcerogenic than its (S)‐enantiomer

Abstract

The most common, and sometimes life-threatening, side-effects associated with the human use of the analgesic, nonsteroidal antiinflammatory drugs (NSAIDs) are gastrointestinal. These include gastritis, ulceration, and severe bleeding. The aryl propionic acid class of NSAIDs are among the most widely used of these drugs in the world, including rac-ibuprofen, rac-flurbiprofen, and rac-ketoprofen. Marketed as racemates, it was assumed that the "inactive" (R)-enantiomers, having no cyclooxygenase inhibiting effect, also had no toxic effect. In a 30-day dose response study of (S)-, (R)-, and rac-flurbiprofen given daily over a range of doses the (R)-isomer alone proved to be without apparent gastrointestinal (GI) toxicity. On the other hand the racemate proved to be 2 to 4 times as ulcerogenic in enantiomerically equivalent doses as the (S)-enantiomer. These results have significant clinical implications.

IUPAC-NIST Solubility Data Series. 102. Solubility of Nonsteroidal Anti-inflammatory Drugs (NSAIDs) in Neat Organic Solvents and Organic Solvent Mixtures

“…[69][70][71] The majority of ibuprofen formulations on the market contain a racemic mixture of dexibuprofen [(+)-ibuprofen] and (À)-ibuprofen. Studies have shown that R-(À)-ibuprofen can be converted to S-(+)-ibuprofen in the body after oral administration.…”

Effects of flurbiprofen enantiomers on pain‐related chemo‐somatosensory evoked potentials in human subjects.

“…The data also suggest that (S)-flurbiprofen could be used to inhibit inflammation and pain in intensive inflammation, while the (R)-enantiomer could be used for the treatment of pain only. Since (R)-flurbiprofen caused less toxicity in rats than the (S)-enantiomer or the racemic compound [1,42], a reduction of gastrointestinal tract side effects might be achieved by employing (R)-flurbiprofen in pain therapy. There is, however, a need to compare the effectiveness and side effects of flurbiprofen enantiomers in patients suffering from different types of painful diseases.…”

Synthesis of Chirally Pure Enantiomers by Lipase

“…The substrate enantiomeric excess, for the Candida rugosa lipase catalyzed reaction at 96 hours and at water activity of 0.65, in n-heptane, isooctane, and n-nonane was found to be 40.9, 93.0, and 50.0 , respectively 77 . The S-enantiomer of flurbiprofen 2-fluoro-a-methyl-1,1 -biphenyl -4-acetic acid possesses most of its antiinflammatory action, but the presence of the R-enantiomer is reported to greatly enhance its gastrointestinal toxicity 107 . A later study reported that R-flurbiprofen is less potent as an analgesic than S-flurbiprofen, but it caused little toxicity in comparison to its antipode 108 .…”

“…Single enantiomers are more important than their racemic form, because some enantiomers in their racemic form are toxic. For example the S-enantiomer of flurbiprofen 2-fluoro-a-methyl-1,1 -biphenyl -4-acetic acid possesses most of its anti-inflammatory action but, if R-enantiomer is also present then it greatly enhances its gastrointestinal toxicity 107 .…”