Metabolism, inversion

A later single-dose study in eight patients with moderate to severe cirrhosis and a PT of 2-5 seconds above the npper limit of normal, showed an approximate doubling of the half-life compared to controls. Metabolic inversion of the inactive R-ibuprofen to the active S-ibupro-fen may also be impaired in hepatic cirrhosis, because the AUC ratio of R- to S-ibuprofen was significantly higher in patients with cirrhosis. Medicinal ibuprofen is supplied as a racemic mixture [39]. 

S. S. Adams, F. Bresloff, and G. G. Mason, "Pharmacological difference between the optical isomers of ibuprofen Evidence for the metabolic inversion of the (-) isomer," /. Pharm. Pharmacol, 28 256-257 (1976). 

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. ... 

A number of recent studies extend the observation of stereoselectivity of drug metabolism. The inactive d-isomer of propanolol was metabolized in rats with a two-fold shorter plasma half-life than l-propanolol . The anti-inflammatory agent l-a-methylfluorene-2-acetic acid was isomerized in dogs to the d-enantiomer , thus being another example of stereospecific metabolic inversion. Whereas the individual R and S enantiomers of 15 were metabolized at similar rates, the half-life of the more active R isomer was prolonged in the racemic mixture, perhaps due to inhibition of metabolism of the R isomer by the S isomer. A similar effect was observed with the R and S enantiomers of amphetamines , which further illustrates that racemates may exhibit a biological profile different from that anticipated on the basis of the activity of the component enantiomers. 

Adams, S. S., Bresloff, P., Mason, C. G. Pharmacological differences between the optical isomers of ibuprofen evidence for metabolic inversion of the (—)-isomer. J. Pharm. Pharmacol. 1976, 28, 256. 

Vickers, S. and C.A. Duncan (1991). Studies on the metabolic inversion of the 6 chiral center of simvastatin. Biochem. Biophys. Res. Commun. 181, 1508-1515. 

Tracy TS, Wirthwein DP, Hall SD. Metabolic inversion of R-ibuprofen. Drug Metab Dispos 1993 21 114-119. 

Tracy, T.S. Hall, S.D. Metabolic inversion of (R)-ibuprofen. Epimerization and hydrolysis of ibuprofenyl-coenzyme A. Drug Metab. Dispos. 1992, 20, 322-327. 

It is well documented [12-16] that a certain proportion of i (—)-ibuprofen might undergo a metabolic inversion in vivo to the active 5(+) enantiomer, as depicted in Fig. 2. The inversion proceeds [17,18] via the stereoselective transformation of the R(—) isomer in the thioester with the coenzyme A, which can be partially teansesterified by endogenous triacylglycerols to be stored in the lipidic tissues as hybrid triglycerides. / -Ibuprofen-CoA is subsequently isomerized to S-ibuprofen-CoA, which is quickly hydrolyzed to ff 5(+)-ibuprofen. This process is irreversible, so that 5 (+)-ibuprofen is not stored in the lipidic tissue. Recently, the possible formation of an (R)-adenylate intermediate prior to the formation of the (R)-coenzyme thio ester has been described as the stereoselective step... 

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