Covalent binding of diflunisal and probenecid to plasma protein in humans: persistence of the adducts in the circulation.

Acyl glucuronide conjugates of carboxylic drugs have been shown over the past decade to be potentially reactive metabolites, undergoing hydrolysis, intramolecular rearrangement and intermolecular transacylation reactions. The present report describes the covalent binding of diflunisal (D) and probenecid (P) to plasma protein of five healthy volunteers who took a 6-day course of oral D with oral P co-administered during the last 2 days. Maximum concentrations of the D- and P-adducts were achieved within one day of cessation of dosing, and were 35 +/- SE 1 and 17 +/- SE 1 ng/mg protein respectively. The D-protein adduct was eliminated from plasma in a biphasic manner, with a terminal half-life of 10.0 +/- SE 0.9 days. In contrast, elimination of the P-protein adduct was monophasic with a half-life of 13.5 +/- SE 0.3 days. The adducts were still measurable in plasma at least one month after the parent reversibly-bound drugs were undetectable. It is not known whether such covalent binding of the drugs, presumably via their acyl glucuronides, could have any biological consequences, such as induction of hypersensitivity reactions.