Pharmacokinetics and Metabolism of a COX-2 Inhibitor, Valdecoxib, in Mice

Abstract

This article is available online at http://dmd.aspetjournals.org ABSTRACT:The pharmacokinetics and metabolism of valdecoxib, a potent cyclooxygenase-2 selective inhibitor, were investigated in mice. Valdecoxib, 4-(5-methyl-3-phenylisoxazol-4-yl)benzenesulfonamide, is a new anti-inflammatory drug that is highly selective for inhibition of the inducible form of cyclooxygenase (COX-2 1 ) in in vitro enzymatic assays (Talley et al., 2000). This drug (BEXTRA, Pharmacia Corporation) was approved recently by the U.S. Food and Drug Administration for the treatment of rheumatoid arthritis, osteoarthritis, and primary dysmenrrhea (Camu et al., 2002;Fricke et al., 2002). Valdecoxib is the second generation COX-2 inhibitor developed by Pharmacia after celecoxib, the first approved COX-2 inhibitor. These new types of anti-inflammatory drugs are developed based on the hypothesis that selective inhibition of COX-2 should decrease inflammation without the adverse gastrointestinal effects associated with inhibition of the constitutive cyclooxygenase (COX-1) (Donnelly and Hawkey, 1997;Pennisi, 1998;Vane et al., 1998). Clinical studies have demonstrated that COX-2 inhibitors lead to a significant reduction in joint pain, joint tenderness/pain, and joint swelling with a statistically-significantly lower incidence of gastric ulceration Simon et al., 1998). Additionally, recent studies demonstrated that COX-2 inhibitors appear to provide some relief for preventing colon cancer and Alzheimer's disease (Elder and Paraskeva, 1998;Hecker, 1998;Pennisi, 1998;Ziegler, 1998).We have recently reported the absorption, distribution, metabolism, and excretion of valdecoxib in humans (Yuan et al., 2002). The primary oxidative metabolic pathways of valdecoxib in humans involved in hydroxylation at either the methyl group to form a hydroxymethyl metabolite or N-hydroxylation at the sulfonamide moiety to form an N-hydroxy metabolite. Further oxidation of the hydroxymethyl metabolite led to the formation of several other phase I metabolites. Oxidative breakdown of the N-hydroxy sulfonamide functional group in the N-hydroxy metabolite led to the formation of corresponding sulfinic acid and sulfonic acid metabolites. The Oglucuronidation of the hydroxymethyl metabolite and N-glucuronidation of valdecoxib were the major metabolites in human urine. The objectives of this study were to determine the total radioactivity recovery in male and female mice following a single oral administration of [ 14 C]valdecoxib at 5 mg/kg, to obtain metabolic profiles in selected mouse plasma RBC, urine, and fecal samples, to identify the major metabolites of valdecoxib, to estimate plasma and RBC pharmacokinetic parameters for total radioactivity, and to examine gender difference in pharmacokinetics of valdecoxib and major metabolites. Materials and Methods Chemicals. Valdecoxib and [14 C]valdecoxib (uniformly labeled at the six carbons of 3-phenyl ring) were synthesized at Pharmacia Corporation (Skokie, IL). The specific activity of [ 14 C]valdecoxib was approximately 5...

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