TY - JOUR T1 - Mechanistic Studies on the Reversible Metabolism of Rofecoxib to 5-Hydroxyrofecoxib in the Rat: Evidence for Transient Ring Opening of a Substituted 2-Furanone Derivative Using Stable Isotope-Labeling Techniques. JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 1614 LP - 1628 VL - 29 IS - 12 AU - Thomas A. Baillie AU - Rita A. Halpin AU - Bogdan K. Matuszewski AU - Leslie A. Geer AU - Cynthia M. Chavez-Eng AU - Dennis Dean AU - Matthew Braun AU - George Doss AU - Allen Jones AU - Tina Marks AU - David Melillo AU - Kamlesh P. Vyas Y1 - 2001/12/01 UR - http://dmd.aspetjournals.org/content/29/12/1614.abstract N2 - Rofecoxib is a potent and highly selective cyclooxygenase-2 inhibitor used for the treatment of osteoarthritis and pain. Following administration of [4-14C]rofecoxib to intact rats, the plasma Cmax (at ∼1 h) was followed by a secondary Cmax (at ∼10 h), which was not observed in bile duct-cannulated rats. Following administration of [4-14C]5-hydroxyrofecoxib to intact or bile duct-cannulated rats, radiolabeled rofecoxib was detected in plasma, and once again a secondary Cmax for rofecoxib was observed (at ∼10 h), which occurred only in the intact animals. These results indicate that reversible metabolism of rofecoxib to 5-hydroxyrofecoxib occurs in the rat and that the process is dependent upon an uninterrupted bile flow. Studies on the contents of the gastrointestinal tract of rats showed that conversion of 5-hydroxyrofecoxib to parent compound occurs largely in the lower intestine. Treatment of rats with [5-18O]5-hydroxyrofecoxib, followed by liquid chromatography-tandem mass spectrometry analyses of plasma samples, confirmed that 5-hydroxyrofecoxib undergoes metabolism to the parent drug, yielding [1-18O]rofecoxib, [2-18O]rofecoxib, and unlabeled rofecoxib. Similarly, treatment with [1,2-18O2]rofecoxib afforded the same three isotopic variants of rofecoxib. These findings are consistent with a metabolic sequence involving 5-hydroxylation of rofecoxib, biliary elimination of the corresponding glucuronide, and deconjugation of the glucuronide in the lower gastrointestinal tract. Reduction of the 5-hydroxyrofecoxib thus liberated yields a hydroxyacid that cyclizes spontaneously to regenerate rofecoxib, which is reabsorbed and enters the systemic circulation. This sequence represents a novel form of enterohepatic recycling and reflects the susceptibility of 5-hydroxyrofecoxib, as well as rofecoxib itself, to reversible 2-furanone ring opening under in vivo conditions. The American Society for Pharmacology and Experimental Therapeutics ER -