Disposition of a Specific Cyclooxygenase-2 Inhibitor, Valdecoxib, in Human

Yuan, Josh; Daichang, Yang; Zhang, Ji Y.; Bible, Roy H.; Karim, Aziz; Findlay, J. W. A.

doi:10.1124/dmd.30.9.1013

Cited by 52 publications

(35 citation statements)

References 12 publications

(7 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These metabolites were also detected in human metabolism studies and were confirmed by the comparison with the synthetic standards (Yuan et al, 2002).…”

Section: M4 M6 and M8 The Mass Spectra Of M4 M6 And M8 Showed [Mmentioning

confidence: 63%

“…However, the oxidative breakdown of the N-hydroxy sulfonamide group in M2 led to the formation of a sulfonic acid metabolite M8, which was detected in mouse urine. Both M2 and M8 were found in human urine (Yuan et al, 2002). Reduction of valdecoxib on the isoxazole ring resulted in the formation of an isoxazole ring-opened metabolite M11.…”

Section: Discussionmentioning

confidence: 99%

“…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.…”

Section: Introductionmentioning

confidence: 99%

“…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.…”

mentioning

confidence: 99%

See 3 more Smart Citations

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

Zhang¹,

Yuan²,

Wang³

et al. 2003

Drug Metab Dispos

Self Cite

View full text Add to dashboard Cite

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...

show abstract

“…These metabolites were also detected in human metabolism studies and were confirmed by the comparison with the synthetic standards (Yuan et al, 2002).…”

Section: M4 M6 and M8 The Mass Spectra Of M4 M6 And M8 Showed [Mmentioning

confidence: 63%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

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

Zhang¹,

Yuan²,

Wang³

et al. 2003

Drug Metab Dispos

Self Cite

View full text Add to dashboard Cite

show abstract

“…VALD chemically is 4-(5-methyl-3-phenyl-4-oxazolyl)benzenesulfonamide, and its chemical structures is shown in (Figure 1). VALD is metabolized primarily by cytochrome P450 2C9 and 3A4 to the pharmacological active hydroxylated metabolite and the carboxylic acid metabolite in humans [7][8][9].…”

Section: Introductionmentioning

confidence: 99%

Potentiometric Sensors for the Determination of Valdecoxib in Pharmaceutical Preparation

Rassi

2015

ILCPA

View full text Add to dashboard Cite

Valdecoxib (VALD) selective electrodes based on VALD-5,6-diamino-2-thiouracil hydrochloride (DTUH) (VALD-DTUH) ion pair in PVC matrix membrane were constructed. The plasticizers used were dibutylphthalate (DBP) (Electrode B) tri-n-butylphosphate (TBP) (electrode C), or dioctylphthalate (DOP) (electrode) A. The electrodes gave the linear range between 6.0×10 −6 -17.9×10 −3 , 2.5×10 −5 -8.3×10 −3 M, M and 2.5×10 −6 -2.0×10 −2 M respectively. The slopes for linear range ranged from 39.29 to 58.76mV/decade with correlation coefficients lying between 0.997, 0.989 and 0.999 respectively. The best detection limit was 1.50×10−6 M for the electrode based on DOP. Selectivity coefficients of VALD related to a number of interfering cation and some organic compounds and excipients were studied using matched potential method (MPM(, and there were negligible interference caused by most of the investigated species. The pH and life time of the electrodes were also studied. The direct determination of VALD shows an average recovery of (100.08-100.61 and 99.75-101.00)% and a mean relative standard deviation of (2.70-0.61 and 2.39-0.56)% for sensor A and B respectively. The results obtained by determination of VALD in tablets using the proposed sensors which comparable favorably with those obtained by spectrophotometric method. Validation of the method shows the suitability of the electrodes for the determination of VALD in pharmaceutical formulation.

show abstract

Principles of Drug Metabolism

Dalvie

Testa

2021

Burger's Medicinal Chemistry and Drug Discovery

View full text Add to dashboard Cite

Metabolism is a complex process that involves enzymatic modification of drugs and xenobiotics and is one of the most important determinants of their fate in the body. Although the drug metabolism is considered a process of detoxification, the products of metabolism can play an important role in the pharmacology and toxicology of the parent drug. Studying the metabolism of newly synthesized molecules is a valuable strategy that allows one to identify the underlying problems, such as “soft spots,” or metabolic activation, that affect the systemic exposure of a molecule and safety and efficacy. Early investigative metabolism of new compounds has helped in assessing the bioactivation potential of these candidates and thus, avoid reactive metabolites or put mitigation strategies in place. Metabolism can also lead to pharmacologically active metabolites. These metabolites can have superior pharmacological, pharmacokinetic, and safety profiles compared to their parent drug and can therefore be developed as drugs. This chapter provides an overview of the enzymes involved in the metabolism of xenobiotics and the different metabolic pathways. An attempt has been made to illustrate these principles with pertinent example with a brief review of topics of potential interests to aspiring medicinal chemists namely, the factors that may influence biotransformation or applications to predict the sites of metabolism. While the medicinal chemists are not expected to possess a deep knowledge of the mechanistic aspects, the hope is that the principles outlined in this chapter will assist them in designing a better drug.

show abstract

Disposition of a Specific Cyclooxygenase-2 Inhibitor, Valdecoxib, in Human

Abstract: 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 [

Cited by 52 publications

References 12 publications

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

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

Potentiometric Sensors for the Determination of Valdecoxib in Pharmaceutical Preparation

Principles of Drug Metabolism

Contact Info

Product

Resources

About