Species-dependent enantioselective glucuronidation of three 2-arylpropionic acids. Naproxen, ibuprofen, and benoxaprofen.

The enantioselective glucuronidation of several racemic 2-arylproprionic acids (naproxen, ibuprofen, and benoxaprofen) was investigated in vitro with immobilized microsomal protein from human, rhesus monkey, and rabbit liver as the source of UDP-glucuronyl-transferases. Human microsomes, solubilized microsomal protein, and immobilized protein all gave comparable enantioselectivity. The diastereomeric glucuronides were separated and quantitated by HPLC and characterized stereochemically by co-elution with glucuronides formed from authentic resolved enantiomers. Conjugation of the carboxylic acid moieties occurred stereoselectively with all three substrates. However, enantioselectivity varied qualitatively and quantitatively with substrate as well as with species. The glucuronidation of (S)-naproxen by human liver enzymes was inhibited in the presence of (R)-naproxen and vice versa. The ratio of the glucuronides of (S)-benoxaprofen to that of (R)-benoxaprofen in rhesus monkey urine varied between individual animals and appeared to change through time as dosing continued. Hydrolysis of the diasteriomeric glucuronides of (R)- and (S)-naproxen was differentially inhibited by addition of 1,4-saccharolactone.