2-Arylpropionic acids, metabolism

Hutt A.J., Kooloobandi A. Hanlon GW. (1993) Microbial metabolism of 2-arylpropionic acids Chiral inversion ofibuprofen and 2-phenylpropionic acid. Chirality, 5, 596-601. 

Transfer of a glucuronic acid moiety from UDP-glucuronic acid is a common reaction in drug metabolism and detoxification pathways. Spahn (1988) described an assay method that is applicable to arylpropionic acids and is capable of separating and quantitating enantiomers. 

Hutt, A.J. Caldwell, J., The metabolic chiral inversion of 2-arylpropionic acids A novel route with pharmacological consequences J. Pharm. Pharmacol. 1983, 35, 693-704. 

J. Caldwell, A. J. Hutt, and S. Foumel-Gigleux, The metabolic chiral inversion and dispositional enantioselecHvity of the 2-arylpropionic acids and their biological consequences," Biochem. Pharmacol., 37 105-114 (1988). 

It is usual in humans for the S(+)-enantiomer of 2-arylpropionic acids to predominate in plasma and for the S(- -)- to R(-)-enantiomeric ratio of plasma concentrations to increase with time after administration of the racemate, which is often attributed to metabolic inversion of the chiral center of the R( )-enantiomers to their S(- -)-antipodes. ° In humans, the S(- -)-enantiomer is generally eliminated more slowly than is the R( )-enantiomer. The extent of chiral inversion of fenoprofen, which has been attributed to the differential rate of formation of the CoA-thioester by hepatic microsomes, varies widely among species. It has been estimated to be 90% in dogs, 80% in sheep, 73% in rabbits, 60% in humans, 42% in rats,f and 38% in horses. ... 

Various arylpropionic acids show similar specificity. For most, if not all, the (5) enantiomer is the pharmacologically active one, whereas the R) enantiomer is usually much less active, although the ratio of iS)/ R) activity varies from drug to drug (and species to species). Only one of these drugs, however, is administered as the separated (S) enantiomer (naproxen, Naprosyn ). Normally these drugs are considered safe, and one cannot readily differentiate between the relative activities of the (S) and (R) forms because the in vivo half-life is very short, typically one or two hours. In patients with impaired renal function, where clearance is much slower, however, problems can arise. From in vivo studies of ibuprofen, it was established that the (S)-(-l-) isomer was responsible for antiinflammatory activity. In vivo, however, the (/ )-(-) isomer may become active because there is stereoselective inversion from R) to (S) (but not from 5 to R) in vivo with a half-life of about two hours. This inversion apparently proceeds by stereoselective formation of the coenzyme A (CoA) ester of the (f )-(-)-arylpropionic acid, followed by epimerization and release of the (S)-(+)-enantiomer. This epimerization is observed in vivo before the oxidative metabolism. Such inversion from (R) to (S) in vivo is also known for fenoprofen and benoxa-profen, and is expected to occur for most of the drugs of this series. ... 

Other important metabolites of O-glucuronidation are acylglucuronides. They are formed by esterification of carboxylic acids with glucuronic acid. Many therapeutic agents such as arylacetic acids (diclofenac, diflunisal), aliphatic acids (valproic acid) and arylpropionic acids (ketoprofen, naproxen) are metabolized as acylglucuronides (Fig. 31.37). 

Figure 14 Mechanism of the metabolic chiral inversion of 2-arylpropionic acid NSAIDs.

Chen, C.S. Chen, T. Shieh, W.R. Metabolic stereoisomeric inversion of 2-arylpropionic acids. On the mechanism of ibuprofen epimerization in rats. Biochemica Biophysica Acta 1990, 1033, 1-6. 

Hanlon, G.W. Kooloobandi, A. Hutt, A. J. Microbial metabolism of 2-arylpropionic acids effect of environmental parameters on the growth of Verticillium lecanii and its metabolism of ibuprofen. J. Appl. Bact. 1994, 76,442-447. 

Mayer, J.M. Bartalucci, C. Maitre, J. Testa, B. Metabolic chiral inversion of anti-inflammatory 2-arylpropionates lack of reaction in liver homogenates, and study of methine proton acidity. Xenobiotica 1988, 18, 533-543. 

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