DISPOSITION AND COVALENT BINDING OF IBUPROFEN AND ITS ACYL GLUCURONIDE IN THE ELDERLY

Ibuprofen is an over-the-counter nonsteroidal anti-inflammatory drug w ith a low incidence of severe adverse reactions, It is metabolized by oxidation to carboxyibuprofen and hydroxyibuprofen and by conjugation to an acyl glucuronide, In vitro studies have indicated that ibuprofen glucuronide is labile and reactive, forming covalent adducts with pro teins, To verify the formation of ibuprofen-protein adducts in vivo, t he pharmacokinetics of ibuprofen glucuronide and its covalent binding to plasma proteins were studied in five elderly patients who received long-term administration of oral doses of ibuprofen. Plasma levels of ibuprofen glucuronide were low relative to those of ibuprofen; the rat io of area under the plasma concentration versus time curve for the gl ucuronide relative to the parent drug was only 4%. Covalent binding of ibuprofen to plasma protein was observed in all patients, correlating well with the area under the plasma concentration versus time curve o f ibuprofen glucuronide (r = 0.966), Compared with reports for other n onsteroidal anti-inflammatory drugs that form acyl glucuronides, plasm a levels of ibuprofen-protein adduct are low during long-term administ ration, The observed lower reactivity in vivo is probably attributable to the greater stability of ibuprofen glucuronide relative to other a cyl glucuronides.