Glucuronidation of 2-arylpropionic acids pirprofen, flurbiprofen, and ibuprofen by liver microsomes.

Acylglucuronide formation from the 2-arylpropionic acids pirprofen, flurbiprofen, and ibuprofen, three nonsteroidal anti-inflammatory drugs (NSAIDs), was investigated in rat liver microsomes using an HPLC method and 14C-labeled UDP-glucuronic acid as co-substrate. Pirprofen was the best substrate of UDP-glucuronosyltransferase with a Vmax/Km of 45.4, as compared with 8.0 and 1.6 for flurbiprofen and ibuprofen, respectively. Glucuronidation of the drugs was significantly increased upon treatment of rats with phenobarbital; 3-methylcholanthrene or clofibrate failed to induce the activity. At the dose of 100 mg/kg body weight for 1, 3, and 5 days, pirprofen was unable to induce its own glucuronidation. However, this treatment caused a transient increase, after 1 day, of several isoform activities monitored with 4-nitrophenol, 1-naphthol, 4-methylumbelliferone, terpenes, and testosterone as substrates. After 3 and 5 days these activities were decreased, especially when glucuronidation of 4-nitrophenol and 4-methylumbelliferone was considered, glucuronidation of the terpenes cis-myrtanol, borneol, nopol, and of testosterone being similar to control values. By contrast to clofibrate, administration of pirprofen to rats decreased bilirubin UDP-glucuronosyltransferase in a time-dependent fashion with a maximal decrease of 59% after 5 days. Treatment of rats with pirprofen also decreased markedly the formation of flurbiprofen glucuronide. Comparison of NSAID glucuronidation between several species indicated that it was most potent in monkeys, dogs, and humans. Cats were also efficient in that respect. Gunn rats, which are genetically deficient in bilirubin glucuronidation, were able to form acylglucuronides from the drugs, thus indicating that these 2-arylpropionic acids were not substrates of the bilirubin isozyme.