Abstract
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.
Footnotes
- Abbreviations used are::
- COX
- cyclooxygenase
- GI
- gastrointestinal tract
- DMSO
- dimethyl sulfoxide
- PEG-400
- polyethylene glycol-400
- TFA
- trifluoroacetic acid
- HPLC
- high-performance liquid chromatography
- MS
- mass spectrometry
- DMF
- dimethylformamide
- AUC
- area under the plasma concentration versus time curve
- LC-MS/MS
- liquid chromatography-tandem mass spectrometry
- Received June 5, 2001.
- Accepted August 15, 2001.
- The American Society for Pharmacology and Experimental Therapeutics
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