PT  - JOURNAL ARTICLE
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
TI  - 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.
DP  - 2001 Dec 01
TA  - Drug Metabolism and Disposition
PG  - 1614--1628
VI  - 29
IP  - 12
4099  - http://dmd.aspetjournals.org/content/29/12/1614.short
4100  - http://dmd.aspetjournals.org/content/29/12/1614.full
SO  - Drug Metab Dispos2001 Dec 01; 29
AB  - 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