Pharmacokinetics and metabolism of a COX-2 inhibitor, valdecoxib, in mice.
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 [(14)C]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 (AUC(0-infinity)) values for valdecoxib and M1 were 3.58 and 0.850 microg. h/ml in males and 2.08 and 1.63 microg. h/ml in females, respectively. The RBC AUC(0-infinity) values for valdecoxib and M1 were 12.1 and 22.6 microg. h/g in males and 6.42 and 35.2 microg. h/g in females, respectively.
Zhang
Ji Y
JY
Global Drug Metabolism, Pharmacia, 4901 Searle Parkway, Skokie, IL 60077, USA. ji.y.zhang@pharmacia.com
Yuan
Josh J
JJ
Wang
Yue-Fen
YF
Bible
Roy H
RH
Breau
Alan P
AP
D000818:Animals; D001711:Biotransformation; D002247:Carbon Isotopes / Q000097:blood / Q000493:pharmacokinetics / Q000652:urine; D002250:Carbon Radioisotopes; D002853:Chromatography, Liquid / Q000295:instrumentation / Q000379:methods; D051546:Cyclooxygenase 2; D004305:Dose-Response Relationship, Drug; D004912:Erythrocytes / Q000187:drug effects / Q000378:metabolism; D005260:Female; D008401:Gas Chromatography-Mass Spectrometry / Q000295:instrumentation / Q000379:methods; D005966:Glucuronidase / Q000378:metabolism; D006868:Hydrolysis; D007527:Isoenzymes / Q000037:antagonists & inhibitors*; D007555:Isoxazoles / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics* / Q000652:urine; D008279:Magnetic Resonance Imaging / Q000295:instrumentation / Q000379:methods; D008297:Male; D008657:Metabolic Clearance Rate; D051379:Mice; D008815:Mice, Inbred Strains; D010949:Plasma / Q000187:drug effects / Q000378:metabolism; D011451:Prostaglandin-Endoperoxide Synthases; D013449:Sulfonamides / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics* / Q000652:urine; D013997:Time Factors; D000096926:Benzenesulfonamides
D002247:Carbon Isotopes; D002250:Carbon Radioisotopes; D051546:Cyclooxygenase 2; D005966:Glucuronidase; D007527:Isoenzymes; D007555:Isoxazoles; D011451:Prostaglandin-Endoperoxide Synthases; D013449:Sulfonamides; C406224:valdecoxib; D000096926:Benzenesulfonamides