Pure enantiomers of 2-arylpropionic acids: tools in pain research and improved drugs in rheumatology.
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.
Brune
K
K
Department of Experimental and Clinical Pharmacology and Toxicology, University of Erlangen-Nuernberg, Germany.
Geisslinger
G
G
Menzel-Soglowek
S
S
D000818:Animals; D006801:Humans; D007052:Ibuprofen / Q000627:therapeutic use; D007660:Ketoprofen / Q000627:therapeutic use; D010146:Pain / Q000188:drug therapy*; D011422:Propionates / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D012106:Research; D012216:Rheumatic Diseases / Q000188:drug therapy*; D013237:Stereoisomerism
D011422:Propionates; D007660:Ketoprofen; D007052:Ibuprofen