STEREOSELECTIVE PROTEIN-BINDING OF NONSTE ROIDAL ANTIINFLAMMATORY DRUGS - PHARMACOLOGICAL CONSEQUENCES

Non steroidal anti-inflammatory drugs (NSAIDs) contain a chiral carbon alpha to carboxyl function. Except for naproxen, chiral NSAIDs are ma rketed for clinical use as racemate, ie an equimolar mixture of the tw o enantiomers R(-) and S(+). However, in vitro studies have shown that the anti-inflammatory activity exists almost solely in the S form. Th e unbound fraction is able to diffuse into tissues and to reach sites of action. It represents also the pharmacological active form. Stereos elective protein binding studies carried out at various concentrations of NSAIDs and albumin are used to evaluate the free fraction of the a ctive enantiomer. Two optical isomers do not interact in the same mann er with proteins and this binding stereoselectivity depends on NSA ID and experimental conditions. Thus, it seems difficult to predict the i n vivo free concentration of each enantiomer and protein binding exper iments should be achieved taking into account the physiopathological p arameters which influence this biological process. This enantioselecti vity is determinant for the pharmacokinetic properties and could be re sponsible of the parameters variation obtained for each enantiomer. It could explain the variability in response to NSAIDs too. In fact, the anti-inflammatory effect is directly function of the free concentrati on of the S isomer. To correlate the NSAID dose with its activity, it should be better to determine this free fraction in the site of action , in particular in the synovial fluid. But the clinical response, as f or example the antalgic effect, remains very far from the pharmacologi cal activity, ie the cyclooxygenase inhibition.