RT Journal Article
SR Electronic
T1 Pharmacokinetics and Metabolism of a COX-2 Inhibitor, Valdecoxib, in Mice
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 491
OP 501
DO 10.1124/dmd.31.4.491
VO 31
IS 4
A1 Ji Y. Zhang
A1 Josh J. Yuan
A1 Yue-Fen Wang
A1 Roy H. Bible, Jr.
A1 Alan P. Breau
YR 2003
UL http://dmd.aspetjournals.org/content/31/4/491.abstract
AB The pharmacokinetics and metabolism of valdecoxib, a potent cyclooxygenase-2 selective inhibitor, were investigated in mice. Valdecoxib was extensively metabolized after a single 5 mg/kg oral administration of [14C]valdecoxib and elimination of unchanged drug was minor (less than 1%) in male and female mice. The total mean percentage of administered radioactive dose recovered was 99.8% in the male mice and 94.7% in the female mice. Sixteen metabolites were identified in mouse plasma, red blood cells, urine, and feces. The main phase I metabolic pathway of valdecoxib in mice involved the oxidation of the 5-methyl group to form the active hydroxymethyl metabolite M1. M1 was further oxidized to the carboxylic acid metabolite M4, which underwent opening of the isoxazole ring to form M6 and M13. Phase II metabolism included glucuronide, glucoside, and methyl sulfone conjugations. M1 was also conjugated with glucuronic acid and glucose to yield M-G and M1-glucose, respectively. Three novel methylsulfone conjugates M20, M21, and M21-G were detected in blood or urine. Valdecoxib and M1 were the major radioactive components in plasma and red blood cells. The plasma area under the curve from zero to infinity (AUC0-∞) values for valdecoxib and M1 were 3.58 and 0.850 μg · h/ml in males and 2.08 and 1.63 μg · h/ml in females, respectively. The RBC AUC0-∞ values for valdecoxib and M1 were 12.1 and 22.6 μg · h/g in males and 6.42 and 35.2 μg · h/g in females, respectively. The American Society for Pharmacology and Experimental Therapeutics