Biochemical zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA Pharmacology, Vol. 37. No. 1. pp. 105-114, 1988. Printed in Great Britain. @X&-2952,& $3.00 + 0.00 @I 1988. Pergamon Journals Ltd. THE METABOLIC CHIRAL INVERSION AND DISPOSITIONAL ENANTIOSELECTIVITY OF THE 2-ARYLPROPIONIC ACIDS AND THEIR BIOLOGICAL CONSEQUENCES JOHN CALDWELL, ANDREW J. HUTT* and SYLVIE FOURNEL-GIGLEUX~ Department of Pharmacology and Toxicoiogy, St. Mary’s Hospital Medical School, London W2 lPG, U.K. *Department of Pharmacy, Brighton Polytechnic, Moulsecoomb, Brighton BN2 4GJ, U.K., and tCentre du M~di~ment, Universitt? de Nancy, 54000 Nancy, France zyxwvutsrqponmlkjihgfedcbaZ Abstrad-The 2-arylpropionic acids are currently an important group of non-steroidal anti-inflammatory agents. They contain a chiral centre, and in oitro studies on inhibition of prostaglandin synthesis show that their activity resides almost exclusively in the S(+)-isomers. However, this stereoselectivity of action is not manifest in uiuo, due to the thus-far-unique unidirectional metabolic inversion of the chiral centre from the inactive R(-)-isomers to the S(+)-antipodes. Available evidence strongly suggests that this reaction proceeds uia the formation of the acyl CoA thioesters of the 2-arylpropionates, but the participation of enzyme(s) in the inversion process remains uncertain. Although the chiral inversion is seemingly a general feature of the fate of 2-arylpropionates, there do occur important combinations of acid and species where the reaction is not extant. The stereochemistry of the chiral centre of these acids also influences other aspects of their disposition, including the oxidative metabolism of the aryl/arylallcyl moiety, glucuronidation of the -COOH group and plasma protein binding, and the importance of certain of these becomes more evident when renal function is impaired. The biological consequences of the metabolic chiral inversion and enantioselective disposition of the 2-arylpropionates have been summa- rized in terms of their implications for the development and use of safer and more effective drugs of this class. Inflammatory diseases of various types commonly occur in the population and non-steroidal drugs able to interfere with the inflammatory process are thus widely used. Currently, the 2arylpropionic acids or “profens” are an important group of non-steroidal anti-in~~matory drugs (NSAIDs), being both widely prescribed and generally perceived as of con- siderable benefit in diseases such as arthritis and rheumatism. Regrettably, there has also been con- siderable emphasis upon the problem of adverse reactions to NSAIDs, and a number of these drugs have been subjected to close scrutiny [l]. Phenyl- butazone has been withdrawn in many countries, and even the toxicity of aspirin has been re-evaluated. Of more recently introduced agents, zomepirac has been withdrawn due to allergenicity, while various profens have given rise to major problems, e.g. benoxaprofen, suprofen and indoprofen. There is widespread recognition of the value of metabolic and pharmacokinetic information in aiding the discernment of mechanisms of drug action, the establishment of concentration~ffect relations~ps and informing safety evaluation. Although con- ventional metabolic and pharmacokinetic studies of profens are in general unhelpful in understanding adverse reactions [2], it has recently become appar- ent that a consideration of the stereochemical aspects of their fate can provide notable insights [2-41. The profens contain a chiral centre, and exhibit optical activity, and thus exist as pairs of (relatively) readily separable stereoisomers (Fig. 1). In general, enantiomers have very similar physiochemical prop erties, and it is hard to distinguish them in an achiral environment [5]. However, when they are allowed to interact with other chiral centres, it is frequently the case that such interactions exhibit a high degree of handedness [5,6]. The body, of course, provides an intensely chiral en~ronment in which the great majority of import~t processes exhibit stereo- specificity [6]. Many critical features of the phar- macology and toxicology of organic compounds arise from their interaction with highly chiral endogenous molecules present in receptors, enzymes etc. [7]. It thus is not surprising that the biological actions of chiral pharmacologically active molecules reside partly or exclusively in one of the enantiomers [7]. The more active is often referred to as the eutomer zyxwvuts RN Si+) COOH COOH i zyxwvutsrqponmlkjihgfedcbaZYXWVUTS C H~ $‘H _A Ar Ar Yl 3 CH3 zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPON Ar C~KDOH Ar FH-COOH CH3 Fig. 1. Stereochemical representations (as flying wedge diagrams) of the R( -)- and S(+)-enantiomers of the 2- arylpropionic acids. zyxwvutsrqponmlkjihgfedcb 105