title: 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.
abstract: Rofecoxib is a potent and highly selective cyclooxygenase-2 inhibitor used for the treatment of osteoarthritis and pain. Following administration of [4-(14)C]rofecoxib to intact rats, the plasma C(max) (at approximately 1 h) was followed by a secondary C(max) (at approximately 10 h), which was not observed in bile duct-cannulated rats. Following administration of [4-(14)C]5-hydroxyrofecoxib to intact or bile duct-cannulated rats, radiolabeled rofecoxib was detected in plasma, and once again a secondary C(max) for rofecoxib was observed (at approximately 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-(18)O]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-(18)O]rofecoxib, [2-(18)O]rofecoxib, and unlabeled rofecoxib. Similarly, treatment with [1,2-(18)O(2)]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.
authors.affiliation: Department of Drug Metabolism, Merck Research Laboratories, West Point, Pennsylvania 19486, USA. tom_baillie@merck.com
authors.forename: T A
authors.initials: TA
authors.lastname: Baillie
authors.forename: R A
authors.initials: RA
authors.lastname: Halpin
authors.forename: B K
authors.initials: BK
authors.lastname: Matuszewski
authors.forename: L A
authors.initials: LA
authors.lastname: Geer
authors.forename: C M
authors.initials: CM
authors.lastname: Chavez-Eng
authors.forename: D
authors.initials: D
authors.lastname: Dean
authors.forename: M
authors.initials: M
authors.lastname: Braun
authors.forename: G
authors.initials: G
authors.lastname: Doss
authors.forename: A
authors.initials: A
authors.lastname: Jones
authors.forename: T
authors.initials: T
authors.lastname: Marks
authors.forename: D
authors.initials: D
authors.lastname: Melillo
authors.forename: K P
authors.initials: KP
authors.lastname: Vyas
mesh_terms: D000818:Animals; D001646:Bile / Q000378:metabolism; D001711:Biotransformation; D002250:Carbon Radioisotopes; D002851:Chromatography, High Pressure Liquid; D016861:Cyclooxygenase Inhibitors / Q000493:pharmacokinetics*; D005663:Furans / Q000378:metabolism; D007408:Intestinal Absorption; D007553:Isotope Labeling; D007783:Lactones / Q000378:metabolism* / Q000493:pharmacokinetics*; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D010103:Oxygen Isotopes; D051381:Rats; D017207:Rats, Sprague-Dawley; D013450:Sulfones; D014018:Tissue Distribution
chemical_list: D002250:Carbon Radioisotopes; D016861:Cyclooxygenase Inhibitors; D005663:Furans; D007783:Lactones; D010103:Oxygen Isotopes; D013450:Sulfones; C116926:rofecoxib; C445439:5-hydroxyrofecoxib