Pure Enantiomers of 2‐Arylpropionic Acids: Tools in Pain Research and Improved Drugs in Rheumatology

Abstract

The mode of action of aspirinlike drugs in pain is widely referred to as inhibition of prostaglandin synthesis. Salicylic acid, however, at low doses, is an analgesic but not a potent anti-inflammatory agent. This "enigma" may be resolved by recent findings employing 2-arylpropionic acids. Pure enantiomers of these chiral drugs show a different pharmacodynamic and pharmacokinetic profile. Using pure enantiomers of flurbiprofen, ibuprofen, and ketoprofen, we could show that (1) R-enantiomers of these drugs are inverted to S-enantiomers to a different degree in different species, including humans, (2) the pharmacokinetic parameters of both pure enantiomers differ in a drug- and a species-specific manner, and (3) both enantiomers exert differential analgesic effects. It appears particularly interesting that R-flurbiprofen, for instance, which is not or only to a small extent inverted in humans and rats, is practically devoid of prostaglandin synthesis inhibition in vitro. Consequently, in line with current thinking, R-flurbiprofen is not toxic to the gastrointestinal tract and shows no anti-inflammatory effects. In contrast to current concepts, however, this enantiomer does exert analgesic activity in different models of pain and nociception. It is concluded that R-flurbiprofen and, possibly, other R-enantiomers of 2-arylpropionic acids may exert novel analgesic effects independently of peripheral prostaglandin synthesis inhibition in inflamed tissue.

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

“…However, the mechanism of the analgesic effects of (R)-flurbiprofen still remains unclear. Possibly, the inhibition of brain cyclooxygenase by (R)-flurbiprofen as shown in rat experiments takes part in this effect [38,39].…”

“…As indicated by our data, the analgesic efficacy of 50 mg (S)-flurbiprofen might be located between that of 50 mg and 100 mg (R)-flurbiprofen. The probably higher analgesic activity of the (S)-enantiomer relative to the (R)-enantiomer might be attributed to the additional cyclooxygenase inhibitory action of the (S)-enantiomer [38,39].…”

Peripheral and/or central effects of racemic‐, S(+)‐ and R(−)‐flurbiprofen on inflammatory nociceptive processes: a c‐Fos protein study in the rat spinal cord

“…To conclude, this comparative study of the e ects of either intravenous or intraplantar S(+)-and R(7)-¯urbiprofen provides further evidence for the increase and/or the development of therapeutical approaches in two main directions: (i) The local administration of S(+)-¯urbiprofen which produced a strong decrease of both the carrageenanevoked spinal c-Fos protein expression and in¯ammatory oedema suggests that such modality of local administration of S(+)-¯urbiprofen, and probably S(+) enantiomers of other profens, with a better availability at the site of in¯ammation could be a useful approach to avoid gastrointestinal sidee ects; (ii) In contrast, the e ects of systemic administration of R(7)-¯urbiprofen despite the fact that it is less potent than S(+)-¯urbiprofen on the carrageenan-evoked spinal c-Fos protein expression and in¯ammatory oedema, but practically devoid of the gastrointestinal site-e ects (Brune et al, , 1992a for review see also Wechter, 1994;Davies et al, 1996) should be preferentially used when local administration is not possible. (1990).…”

“…of S(+)-urbiprofen, but not R(7)-¯urbiprofen, with the carrageenan model of in¯ammation . In contrast to S(+)-¯urbiprofen, R(7)-¯urbiprofen did not cause signi®cant mucosal damage in the gastro-intestinal tract after oral administration in the rat (Brune et al, , 1992a. Behavioural studies have demonstrated that both S(+) and R(7) enantiomers of¯urbiprofen have antinociceptive e ects 2 Author for correspondence.…”

“…Interestingly, a more recent in vitro study has demonstrated an inhibition of the capsaicininduced current by NSAIDs, such as acetylsalicylic acid, salicylic acid and diclofenac, in rat dorsal root ganglion neurons (Kress et al, 1996). These authors suggest that since the sensitivity to capsaicin is speci®c for nociceptors the inhibitory action via capsaicin receptors may represent a new and potentially important mechanism of the analgesic action of NSAIDs.Finally, for R(7)-¯urbiprofen, we cannot totally exclude an additional mechanism of action by chiral inversion to the S(+)-enantiomer despite the limited extent of enantiomeric bioinversion in the rat (Jamali et al, 1988;Menzel-Soglowek et al, 1992; for review see also Williams, 1990).To conclude, this comparative study of the e ects of either intravenous or intraplantar S(+)-and R(7)-¯urbiprofen provides further evidence for the increase and/or the development of therapeutical approaches in two main directions: (i) The local administration of S(+)-¯urbiprofen which produced a strong decrease of both the carrageenanevoked spinal c-Fos protein expression and in¯ammatory oedema suggests that such modality of local administration of S(+)-¯urbiprofen, and probably S(+) enantiomers of other profens, with a better availability at the site of in¯ammation could be a useful approach to avoid gastrointestinal sidee ects; (ii) In contrast, the e ects of systemic administration of R(7)-¯urbiprofen despite the fact that it is less potent than S(+)-¯urbiprofen on the carrageenan-evoked spinal c-Fos protein expression and in¯ammatory oedema, but practically devoid of the gastrointestinal site-e ects (Brune et al, , 1992a for review see also Wechter, 1994;Davies et al, 1996) should be preferentially used when local administration is not possible. (1990).…”