Nonsteroidal anti-inflammatory drugs (
NSAIDs), used for the treatment of
pain and
inflammation, are eliminated primarily through conjugation with polar
sugar moieties to form
glucuronides. Glucuronidation is catalyzed by the
UDP-glucuronosyltransferases (UGT) superfamily. An inverse relationship may exist between glucuronidation activity and
NSAID efficacy; however, specific UGTs catalyzing conjugation of the structurally diverse
NSAIDs have yet to be identified systematically. Therefore,
NSAID glucuronidation activity by 12 individually expressed UGTs was investigated by liquid chromatography-tandem mass spectrometry. The relative rates of
NSAID glucuronidation varied among UGT
enzymes examined, demonstrating specificity of the individual UGTs toward selected
NSAIDs. Kinetic parameters were determined for expressed UGT Supersomes and compared with parameters determined in pooled human liver microsomes (HLMs). Comparison of K(m) values suggested roles for UGTs 1A3 and 2B7 in
indene glucuronidation and UGTs 1A9, 2B4, and 2B7 in profen glucuronidation. Inhibitory studies in pooled HLMs support the role of UGTs 1A1, 1A3, 1A9, 2B4, and 2B7 in the glucuronidation of
ibuprofen,
flurbiprofen, and
ketoprofen.
Bilirubin did not inhibit
indomethacin or
diclofenac glucuronidation, suggesting that UGT1A1 was not involved in catalysis.
Imipramine did not inhibit glucuronidation of
sulindac,
sulindac sulfone,
indomethacin, or
naproxen in pooled HLMs, suggesting that UGT1A3 was not a principal hepatic catalyst. Nevertheless, multiple UGT
enzymes, most notably UGTs 1A1, 1A9, 2B4, and 2B7, seem to be involved in the hepatic catalysis of
NSAID glucuronidation.