Oxidative bioactivation of the lactol prodrug of a lactone cyclooxygenase-2 inhibitor

The lactol derivative of a lactone cyclooxygenase-2 inhibitor (DFU) was eva luated in vivo and in vitro for its potential suitability as a prodrug, DFU -lactol was found to be 10 to 20 times more soluble than DFU in a variety o f aqueous vehicles. After administration of DFU-lactol at 20 mg kg(-1) p.o. in rats, a C-max of 7.5 mu M DFU was reached in the plasma. After oral adm inistration, the ED(50)s of DFU-lactol in the carrageenan-induced paw edema and lipopolysaccharide-induced pyresis assays in rats are comparable with the ED(50)s observed when dosing with DFU. Incubations of DFU-lactol with r at and human hepatocytes demonstrated that the oxidation of DFU-lactol can be mediated by liver enzymes and that a competing pathway is direct glucuro nidation of the DFU-lactol hydroxyl group. Assays with subcellular fraction s from rat liver indicated that most of the oxidation of DFU-lactol occurs in the cytosolic fraction and requires NAD(P)(+). Human liver cytosol can a lso support the oxidation of DFU-lactol to DFU when NAD(P)(+) is added to t he incubations. Fractionation of human liver cytosolic proteins showed that at least three enzymes are capable of efficiently effecting the oxidation of DFU-lactol to DFU. Incubations with commercially available dehydrogenase s suggest that alcohol and hydroxysteroid dehydrogenases are involved in th is oxidative process. These data together suggest that lactols may represen t useful prodrugs for lactone-containing drugs.