The disposition of ibuprofen and ibufenac, an analog of ibuprofen with a history of severe adverse reactions, was investigated in Rhesus monkeys after oral administration. Plasma concentrations of the parent drugs and their glucuronides were measured by a direct HPLC method. Ibuprofen and ibufenac were rapidly absorbed and metabolized to their acyl glucuronides. The pharmacokinetic parameters of ibuprofen and ibufenac exhibited notable interanimal variability. Ibufenac tended to have a higher area under the plasma concentration vs. time curve (AUC), and its apparent clearance was lower. The plasma levels of acyl glucuronides were lower than parent drugs; the ratio of AUC in plasma for glucuronide/parent drug was 22.8% and 10.5% for ibuprofen and ibufenac, respectively. The degradation of ibufenac glucuronide in vitro was faster than ibuprofen glucuronide in aqueous buffer, human serum albumin, and human plasma solutions. Covalent binding of parent drug to protein via the acyl glucuronides was observed both in vitro and in vivo. The maximum protein adduct formed in vivo with ibufenac was 60% higher than found for ibuprofen, although exposure in plasma to its reactive acyl glucuronide, as measured by AUC, was lower. These data indicate that ibufenac glucuronide is a more reactive metabolite than ibuprofen glucuronide in vitro and in vivo.