Racemization ibuprofen, metabolic

Ibuprofen is an interesting case, in that the (5)-(+)-form is an active analgesic, but the ( )-(—)-enantiomer is inactive. However, in the body there is some metabolic conversion of the inactive (I )-isomer into the active (5 )-isomer, so that the potential activity from the racemate is considerably more than 50%. Box 10.11 shows a mechanism to account for this isomerism. 

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]. 

An unique example of stereoisomer selective tissue uptake of stereoisomers is noted with NSAIDs. The R enantiomer of ibuprofen shows preferential uptake into fat following the administration of the racemate and individual isomersJ However, this apparent difference in fat distribution is probably a consequence of the selective metabolic uptake and formation of the coenzyme A thioester of the R isomer, which does not occur with the S isomer. 

The medication with the active S(+)-ibuprofen instead of the racemic (R,S)-ibuprofen is advantageous due to lower dose rates needed, lower loadings in metabolism and no inversion from the R(—)- to the S(+)-form. 

Metabolic resolution of the racemic mixture has been reported using Verticillium lecanii [58]. This microorganism is able to grow on the racemic (i ,5)-ibuprofen, giving a product mixture enriched in the S isomer SIR = 2), after 14 days at pH = 7.0 and 24 C. 

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