Abstract
The disposition and metabolism of rofecoxib, a selective cyclooxygenase-2 inhibitor, were examined in healthy human subjects and in cholecystectomy patients. After oral administration of [14C]rofecoxib (125 mg, 100 μCi) to healthy subjects, the mean concentrations of total radioactivity and rofecoxib in plasma as a function of time indicated that thetmax was achieved at 9 h postdose. After tmax, levels of both radioactivity and rofecoxib decreased in a parallel, exponential fashion (effectivet1/2 ≈ 17 h). A similar result was obtained after oral administration of [14C]rofecoxib (142 mg, 100 μCi) to cholecystectomy patients equipped with an L-tube. In healthy subjects, radioactivity was recovered predominantly from the urine (71.5% of dose), with a small amount excreted in feces (14.2%). In patients with an L-tube, half the radioactive dose was recovered in feces, with a lesser amount excreted in urine (28.8%) and a negligible fraction in bile (1.8%). Rofecoxib underwent extensive metabolism in humans, and very little parent drug was recovered unchanged in urine (<1%). Products resulting from both oxidative and reductive pathways were identified by a combination of 1H NMR and liquid chromatography-tandem mass spectrometry analyses, and included rofecoxib-3′,4′-trans-dihydrodiol, 4′-hydroxyrofecoxib-O-β-d-glucuronide, diastereomeric 5-hydroxyrofecoxib-O-β-d-glucuronide conjugates, 5-hydroxyrofecoxib, rofecoxib-erythro-3,4-dihydrohydroxy acid, and rofecoxib-threo-3,4-dihydrohydroxy acid. Interconversion of rofecoxib and 5-hydroxyrofecoxib appeared not to be a quantitatively important pathway of rofecoxib disposition in human subjects, in contrast to previous findings in rats.
Footnotes
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↵1 Present address: Wyeth-Ayerst Pharmaceuticals, 500 Arcola Road, S3414, Collegeville, PA 19426-3930.
- Abbreviations used are::
- COX-2
- cyclooxygenase-2
- AUC
- area under the plasma concentrations versus time curve
- Cmax
- maximum plasma concentration
- CH3CN
- acetonitrile
- DHHA
- dihydrohydroxy acid
- DMSO-d6
- deuterated dimethyl sulfoxide
- DPS
- disintegrations per second
- HPLC
- high performance liquid chromatography
- ICG
- indocyanine green
- LC
- liquid chromatography
- MS/MS
- tandem mass spectrometry
- MeOH
- methanol
- NSAID
- nonsteroidal anti-inflammatory drug
- p.o.
- peroral
- TFA
- trifluoroacetic acid
- tmax
- time of maximum plasma concentration
- Received September 14, 2001.
- Accepted February 13, 2002.
- The American Society for Pharmacology and Experimental Therapeutics
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