Human lung is a major target organ for all inhaled drugs, environmental toxicants and carcinogens. Recent hypotheses suggesting a role for environmental toxicants in the pathogenesis of lung diseases, such as lung cancer and chronic obstructive pulmonary disease have stimulated interest in research on the xenobiotic metabolizing capability of the lung. Many of the compounds associated with these diseases require enzymatic activation to exert their deleterious effects on pulmonary cells. Interindividual differences in in situ activation and inactivation of xenobiotics may contribute to the risk of developing of lung diseases associated with these compounds. The major xenobiotic metabolizing enzymes, including both phase I and phase II enzymes, have been detected in animal and human lung tissues. Although the lung cytochrome P450 (CYP) and other xenobiotic metabolizing enzymes share many common features with those present in other tissues such as liver, kidney and gut, there are some distinctive differences. It is evident from the studies carried out to date CYP1A1, 1B1, 2A13, 2F1, 2S1 and 4B1 are preferentially expressed in the lung together with CYP2E1 and 3A5. This review provides a detailed picture of major xenobiotic-metabolizing phase I (CYPs, epoxide hydrolases, flavin monooxygenases, etc.) and phase II enzymes (conjugation enzymes, including several transferases) expressed in human lung. The roles of individual metabolizing enzymes and their genetic polymorphisms are also discussed.
ABSTRACT:Valdecoxib is a potent and specific inhibitor of cyclooxygenase-2, which is used for the treatment of rheumatoid arthritis, osteoarthritis, and the dysmenorrhea pain. Eight male human subjects each received a single 50-mg oral dose of [
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...
ABSTRACT:O-Glucuronidation of 5-hydroxyrofecoxib is the major biotransformation pathway of rofecoxib in human, rat, and dog. The glucuronide conjugate is also involved in the reversible metabolism of rofecoxib in rat and human. Atypical bimodal phenomena were observed in their plasma concentration-time curves with a large variability among different human subjects. It is unclear which family members of human UDP-glucuronosyltransferases (UGT) are involved in the formation of the glucuronide. O-Glucuronidation ) and is marketed by Merck as an anti-inflammatory drug (VIOXX) for the treatment of arthritis and pain Prasitet al., 1999). The absorption, distribution, metabolism, and excretion of rofecoxib in rat, dog, and human have been reported (Halpin et al., 2000(Halpin et al., , 2002. Rofecoxib was extensively metabolized with the major metabolites as 5-hydroxyrofecoxib and its O-glucuronide conjugate. In the rat, an unusual feature of the plasma concentration versus time profile for rofecoxib following oral administration was the presence of a distinct second C max . Similar phenomena were also observed in human pharmacokinetic profiles with a large variability among different subjects. It was suggested that the atypical bimodal phenomena in plasma concentration-time curves were due to reversible metabolism of 5-hydroxyrofecoxib to rofecoxib (Baillie et al., 2001). The 5-hydroxyrofecoxib was metabolized to its glucuronide conjugate and excreted in bile. The glucuronide metabolite was deconjugated in the lower gastrointestinal tract, resulting in 5-hydroxyrofecoxib. Reduction of the 5-hydroxyrofecoxib formed a hydroxyacid that cyclized spontaneously to regenerate rofecoxib, which was reabsorbed and entered the systemic circulation. The second C max was due to reabsorption of rofecoxib formed from 5-hydroxyrofecoxib glucuronide in the lower gastrointestinal tract.Since O-glucuronidation of 5-hydroxyrofecoxib plays a major role in biotransformation and reabsorbtion of rofecoxib in human, it is interesting to identify human UGT enzymes responsible for the glucuronidation of 5-hydroxyrofecoxib. To date no human UGT isoform responsible for the glucuronidation of 5-hydroxyrofecoxib has been reported. The primary goal of the present investigation was to determine which human UGT isoforms are responsible for the glucuronidation of 5-hydroxyrofecoxib and to understand the mechanism of high variability in pharmacokinetic patterns in human subjects. 5-Hydroxyrofecoxib was incubated with human liver microsomes and eight cDNA expressed human UGT isoforms from 1A and 2B subfamilies that are involved in xenobiotic metabolism (Mackenzie et al., 1997;Jedlitschky et al., 1999). The incubated samples were analyzed by LC-MS coupled with UV detection. For active UGT isoforms, kinetic parameters were determined and compared with those determined for human liver microsomes in an attempt to better explain the variation in clearance of the compound.
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