DISPOSITION AND REACTIVITY OF IBUPROFEN AND IBUFENAC ACYL GLUCURONIDES IN-VIVO IN THE RHESUS-MONKEY AND IN-VITRO WITH HUMAN SERUM-ALBUMIN

The disposition of ibuprofen and ibufenac, an analog of ibuprofen with a history of severe adverse reactions, was investigated in Rhesus mon keys after oral administration, plasma concentrations of the parent dr ugs and their glucuronides were measured by a direct HPLC method, Ibup rofen and ibufenac were rapidly absorbed and metabolized to their acyl glucuronides. The pharmacokinetic parameters of ibuprofen and ibufena c exhibited notable interanimal variability, Ibufenac tended to have a higher area under the plasma concentration vs, time curve (AUG), and its apparent clearance was lower, The plasma levels of acyl glucuronid es were lower than parent drugs; the ratio of AUC in plasma for glucur onide/parent drug was 22.8% and 10.5% for ibuprofen and ibufenac, resp ectively, 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 vi a the acyl glucuronides was observed both in vitro and in vivo, The ma ximum 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 AUG, was lower, These data indicate that i bufenac glucuronide is a more reactive metabolite than ibuprofen glucu ronide in vitro and in vivo.