Stereoselective Disposition — Basis for Variability in Response to NSAID’s

Interindividual variability in the enantiomeric disposition of ibuprofen following the oral administration of the racemic drug to healthy volunteers

“…14,15 The formation of such "hybrid triglycerides may result in accumulation of these agents and possible toxicity due to their effects on membrane function and lipid It is of interest to note that pirprofen, ibuprofen, and tiaprofenic acid, but not naproxen, inhibit the mitochondrial P-oxidation of palmitic acid in mouse liver preparations." This finding is of particular interest, as the first three compounds were investigated as racemic mixtures, while naproxen was examined as the pure S-enantiomer, and it has been suggested that the inhibition of oxidation may be associated with the mechanism of chiral in~ersi0n.l~ Ibuprofen [R,S-2-(4-isobutylphenyl)propionic acid] is an important NSAID of the profen group and was the first compound of this series for which large differences in the in vitrolin vivo activity of the individual enan-tiomers was observed"; stereoselective metabolism and metabolic chiral inversion in man were re-portedlsp21 and stereoselective incorporation into triglycerides was shown.14 It has been suggested that drug stereochemistry may be an important factor in an individual's therapeutic response to an NSAID22, 23 and it has been pointed out previously7 that with respect to chiral inversion "interindividual variation with consequent variation in response" may well occur. With (R)-ibuprofen, for example, the extent of variation in inversion in healthy volunteers is between 49 and 71% of the dose.…”

Ibuprofen and Paracetamol: Relative Safety in Non-prescription Dosages

“…There is, therefore, a perception that this drug is less effective than more potent NSAIDs, although it is equipotent with other NSAIDs in paediatric rheumatic diseases (Hollingworth 1993). Stereoselective metabolism of ibuprofen occurs in man; the prostaglandin synthesis inactive form, R(-), is approximately 30-60% metabolized to the prostaglandin synthesis active form, the S(+) enantiomer (Williams & Day 1985;Caldwell & Hutt 1987;Rudy et a1 1991;Geisslinger et a1 1993) and this has been claimed to account for some variability in response to the drug (Williams & Day 1985;Geisslinger et a1 1993). The intrasubject variability in therapeutic response to ibuprofen is, however, relatively low (Wagner & Vogtle-Junkert 1996).…”

“…The metabolic conversion of R(-) ibuprofen to its S(+) enantiomer which occurs in liver, intestine and adipose tissue (Williams & Day 1985;Williams et a1 1986;Jeffrey et a1 1991;Menzel-Soglowek et a1 1993;Shirley et a1 1994;Tracy et a1 1993) proceeds by an acyl-coenzyme-A intermediate which can itself lead to the formation of triglyceride derivatives, because this involves part of the normal metabolic route of triglyceride formation and metabolism. Although there has been interest in the biochemistry of this reaction, the suggested relationship to liver or other toxicities (Boelsterli et a1 1995) has not been established.…”

Role of racemization in optically active drugs development

“…64,65,69 In various animal species and humans, ibuprofen was most widely studied with unidirectional chiral inversion. 31,[63][64][65][69][70][71][72][73][74][75][76][77] The unidirectional chiral inversion of R-fenoprofen to its active antipode, with high interspecies changes in the inversion magnitude, was reported in rat, 6,78-80 guinea pig, 80,81 cat 82 and humans. 83,84 In rats 85 and humans, 86 benoxaprofen showed stereospecific inversion from R-to S-enantiomer with high inversion rate in rats than humans.…”