Stereoselective enzymatic hydrolysis of various ester prodrugs of ibuprofen and flurbiprofen in human plasma.
The hydrolysis kinetics of various alkyl, glycolamide, aminoethyl, and 2-(1-imidazolyl)ethyl esters of ibuprofen and flurbiprofen in 80% human plasma were investigated using a direct high-performance liquid chromatographic assay for the enantiomers of these acids. In each case, the R-isomer ester was found to undergo faster plasma-catalyzed hydrolysis than the corresponding S-isomer. The difference in the hydrolysis rates between the enantiomeric forms ranged from a factor of 1.4 for the N,N-diethylglycolamide ester of ibuprofen to a factor of 50 and 25 for the 2-(1-imidazolyl)ethyl ester of ibuprofen and flurbiprofen, respectively. Therefore, enantioselective differences in plasma-catalyzed ester prodrug hydrolysis must be taken into account when evaluating prodrugs of racemic mixtures of chiral drugs.
Mørk
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Royal Danish School of Pharmacy, Department of Pharmaceutical Chemistry, Copenhagen.
Bundgaard
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H
D004952:Esters; D005480:Flurbiprofen / Q000031:analogs & derivatives / Q000097:blood*; D006801:Humans; D006868:Hydrolysis; D007052:Ibuprofen / Q000031:analogs & derivatives / Q000097:blood*; D011355:Prodrugs / Q000378:metabolism*
D004952:Esters; D011355:Prodrugs; D005480:Flurbiprofen; D007052:Ibuprofen