celecoxib, Celebrex
Liquid chromatographic-mass spectrometric determination of celecoxib in plasma using single-ion monitoring and its use in clinical pharmacokinetics.

Abdel-Hamid M, Novotny L, Hamza H.

Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kuwait University, Safat. abdel-hamid hsc.kuniv.edu.kw

Celecoxib is a cyclooxygenase-2 specific inhibitor, that has been recently and intensively prescribed as an anti-inflammatory drug in rheumatic osteoarthritis. A robust, highly reliable and reproducible liquid chromatographic-mass spectrometric assay is developed for the determination of celecoxib in human plasma using sulindac as an internal standard. The run cycle-time is <4 min. The assay method involved extraction of the analytes from plasma samples at pH 5 with ethyl acetate and evaporation of the organic layer. The reconstituted solution of the residue was injected onto a Shim Pack GLC-CN, C18 column and chromatographed with a mobile phase comprised of acetonitrile-1% acetic acid solution (4:1) at a flow-rate of 1 ml/min. The mass spectrometer (LCQ Finnigan Mat) was programmed in the positive single-ion monitoring mode to permit the detection and quantitation of the molecular ions of celecoxib and sulindac at m/z 382 and 357, respectively. The peak area ratio of celecoxib/sulindac and concentration are linear (r2>0.994) over the concentration range 50-1000 ng/ml with a lowest detection limit of 20 ng/ml of celecoxib. Within- and between-day precision are within 1.58-4.0% relative standard deviation and the accuracy is 99.4-107.3% deviation of the nominal concentrations. The relative recoveries of celecoxib from human plasma ranged from 102.4 to 103.3% indicating the suitability of the method for the extraction of celecoxib and I.S. from plasma samples. The validated LC-MS method has been utilized to establish various pharmacokinetic parameters of celecoxib following a single oral dose administration of celecoxib capsules in two selected volunteers.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11334356&dopt=Abstract celecoxib, Celebrex



celecoxib, Celebrex
In-vitro metabolism of celecoxib, a cyclooxygenase-2 inhibitor, by allelic variant forms of human liver microsomal cytochrome P450 2C9: correlation with CYP2C9 genotype and in-vivo pharmacokinetics.

Tang C, Shou M, Rushmore TH, Mei Q, Sandhu P, Woolf EJ, Rose MJ, Gelmann A, Greenberg HE, De Lepeleire I, Van Hecken A, De Schepper PJ, Ebel DL, Schwartz JI, Rodrigues AD.

Drug Metabolism, Merck Research Laboratories, West Point, PA, USA. cuyue_tang merck.com

In-vitro studies were conducted to assess the impact of CYP2C9 genotype on the metabolism (methyl hydroxylation) and pharmacokinetics of celecoxib, a novel cyclooxygenase-2 inhibitor and CYP2C9 substrate. When compared to cDNA-expressed wild-type CYP2C9 (CYP2C9*1), the Vmax/Km ratio for celecoxib methyl hydroxylation was reduced by 34% and 90% in the presence of recombinant CYP2C9*2 and CYP2C9*3, respectively. These data indicated that the amino acid substitution at position 359 (Ile to Leu) elicited a more pronounced effect on the metabolism of celecoxib than did a substitution at position 144 (Arg to Cys). The Vmax/Km ratio was also decreased in microsomes of livers genotyped CYP2C9*1/*2 (47% decrease, mean of two livers), or CYP2C9*1/*3 (59% decrease, one liver). In all cases, these changes were largely reflective of a decrease in Vmax, with a minimal change in Km. Based on simulations of the in-vitro data obtained with the recombinant CYP2C9 proteins, it was anticipated that the pharmacokinetics of celecoxib (as a much as a five-fold increase in plasma AUC) would be altered (versus CYP2C9*1/*1 subjects) in subjects genotyped heterozygous or homozygous for the CYP2C9*2 (Cys144) or CYP2C9*3 (Leu359) allele. In a subsequent clinical study, the AUC of celecoxib was increased (versus CYP2C9*1/*1 subjects) approximately 2.2-fold (range, 1.6-3-fold) in two CYP2C9*1/*3 subjects and one CYP2C9*3/*3 subject receiving a single oral dose (200 mg) of the drug. In contrast, there was no significant change in celecoxib AUC in two subjects genotyped CYP2C9*1/*2.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11337938&dopt=Abstract celecoxib, Celebrex



celecoxib, Celebrex
Renal safety of combined cyclooxygenase 2 (COX-2) inhibitor and angiotensin II receptor blocker administration in mild volume depletion.

Kistler T, Ambuhl PM.

Renal Division, University Hospital, Zurich, Switzerland.

PRINCIPLES: Drugs that either inhibit prostaglandin synthesis or antagonise angiotensin II effects are likely to impair renal function, especially in patients with an activated renin-angiotensin-aldosterone system. Of the former, nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used, and newer agents with cyclooxygenase 2 (COX-2) specific inhibition may have fewer renal side effects compared to non-selective NSAIDs. We therefore investigated whether combination of a COX-2 inhibitor with an angiotensin II subtype 1 (AT1) receptor blocker is safe with regard to preservation of normal renal function in a state of slight volume contraction. METHODS: Mild volume depletion was induced by a salt-restricted diet in 5 healthy volunteers who were then given a single dose of 400 mg celecoxib, a COX-2 inhibitor, alone or in combination with 150 mg irbesartan, an AT1 receptor blocker. Glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) were determined by measuring inulin and PAH clearance respectively, along with plasma renin activity (PRA) and urinary electrolyte excretion before and over 100 minutes after drug administration. RESULTS: PRA was high prior to drug administration, indicating slight salt depletion, and dropped by 65% after intake of celecoxib alone (p = 0.008) but only by 25% after combined intake with irbesartan (p = n.s.). GFR was not affected either by celecoxib alone or by combined administration with irbesartan. In contrast, ERPF increased by 28% 80 minutes after simultaneous drug intake (p = 0.029), but not after celecoxib alone. Renal sodium and potassium excretion did not significantly change under celecoxib alone or in combination with irbesartan. CONCLUSION: Selective COX-2 inhibition by celecoxib in combination with an AT1 receptor blocker (irbesartan) has no acute adverse effects on renal haemodynamics and renal salt handling in slightly volume-depleted subjects with normal renal function. Moreover, our data obtained in humans appear to confirm the co-regulatory interaction of COX-2 and angiotensin II in the control of renin release, as suggested by animal studies.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11345810&dopt=Abstract celecoxib, Celebrex



celecoxib, Celebrex
Fructooligosaccharide associated with celecoxib reduces the number of aberrant crypt foci in the colon of rats.

Buecher B, Thouminot C, Menanteau J, Bonnet C, Jarry A, Heymann MF, Cherbut C, Galmiche JP, Blottiere HM.

Centre de Recherche en Nutrition Humaine de Nantes, INSERM U539, CHU Hotel-Dieu, 44035 Nantes, France.

According to Burkitt's hypothesis, dietary fibres may protect against the development of colorectal cancer. In rats, studies have shown that only butyrate-producing fibres are protective. In parallel, in humans, non-steroidal anti-inflammatory drugs, which target cyclooxygenases, have been shown to display a protective effect against colorectal cancer. Among them, COX-2-selective inhibitors which present less side effects than non-selective agents, are promising as chemopreventive agents. Our aim was to analyse the effect of an association between butyrate-producing fibres and the COX-2 inhibitor on the development of aberrant crypt foci (ACF) in rats. Fisher F344 rats were fed with (1) a standard low fibre control diet; (2) the standard diet supplemented with 1500 ppm celecoxib; (3) a diet supplemented with 6% fructo-oligosaccharide (FOS); and (4) a diet with both celecoxib and FOS. Three weeks later, the rats were injected twice with azoxymethane and the number of ACF was determined 15 weeks later. In the control group, 43.8 +/- 6.4 ACF were found. This number was not significantly modified by the addition of FOS or celecoxib alone to the diet. However, the association of FOS and celecoxib resulted in a 61% reduction in the number of ACF (P < 0.01). The number of aberrant crypt per foci was also reduced. Thus, although no significant effect of celecoxib or FOS alone was identified, the association of butyrate-producing fibre and celecoxib was effective in preventing the development of ACF. This preliminary study argues for a strong protective effect of such an association which deserves further studies.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14971826&dopt=Abstract celecoxib, Celebrex



celecoxib, Celebrex
Targeting cyclooxygenase 2 and HER-2/neu pathways inhibits colorectal carcinoma growth.

Mann M, Sheng H, Shao J, Williams CS, Pisacane PI, Sliwkowski MX, DuBois RN.

Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee 37232-2279, USA.

BACKGROUND & AIMS: The cyclooxygenase 2 (COX-2) and ErbB/HER pathways are important modulators of cancer cell growth. We sought to determine the effects of treatment with a specific COX-2 inhibitor and/or a monoclonal antibody against the ErbB receptor subtype HER-2/neu on carcinoma cell growth. METHODS: A cell-proliferation assay was used to determine the response of HCA-7 cells to the HER-3/HER-4 ligand heregulin beta-1 (HRGbeta-1). Both in vitro and in vivo assays were used to determine the effects of the selective COX-2 inhibitor, celecoxib, and/or an anti-HER-2/neu monoclonal antibody (either Herceptin [Genetech Inc., S. San Francisco, CA] or 2C4) on cell growth. RESULTS: HCA-7 cells express HER-2/neu messenger RNA and protein, and exposure of these cells to HRGbeta-1 results in a significant stimulation of cell growth. Celecoxib or Herceptin inhibits HCA-7 cell growth in vitro and in vivo. Combination therapy with celecoxib plus Herceptin or celecoxib plus 2C4 resulted in additive effects that resulted in almost complete inhibition of tumor growth. CONCLUSIONS: Combined treatment with COX-2 and HER-2/neu inhibitors more effectively reduces colorectal carcinoma growth than either agent alone. Therefore, targeting of both the COX-2 and ErbB signaling pathways may represent a novel approach for the treatment and/or prevention of colorectal cancer in humans.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11375952&dopt=Abstract celecoxib, Celebrex



celecoxib, Celebrex
Cyclooxygenase-2 promotes human cholangiocarcinoma growth: evidence for cyclooxygenase-2-independent mechanism in celecoxib-mediated induction of p21waf1/cip1 and p27kip1 and cell cycle arrest.

Han C, Leng J, Demetris AJ, Wu T.

Department of Pathology, University of Pittsburgh School of Medicine, Presbyterian University Hospital, 200 Lothrop Street, Pittsburgh, PA 15213, USA.

The expression of cyclooxygenase-2 (COX-2) is increased in human cholangiocarcinoma. However, the biologic function and molecular mechanisms of COX-2 in the control of cholangiocarcinoma cell growth have not been well established. This study was designed to examine the direct effect of COX-2 and its inhibitor celecoxib on the growth of human intrahepatic cholangiocarcinoma cells. Overexpression of COX-2 or treatment with prostaglandin E(2) (PGE(2)) enhanced human cholangiocarcinoma cell growth, whereas antisense depletion of COX-2 in these cells decreased PGE(2) production and inhibited growth. These findings demonstrate a direct role of COX-2-mediated PGE(2) in the growth regulation of human cholangiocarcinoma cells. Furthermore, the COX-2 inhibitor celecoxib induced a dose-dependent inhibition of cell growth, cell cycle arrest at the G(1)-S checkpoint, and induction of cyclin-dependent kinase inhibitors p21(waf1/cip1) and p27(kip1). However, the high concentration of celecoxib (50 micro M) required for inhibition of growth, the incomplete protection of celecoxib-induced inhibition of cell growth by PGE(2) or COX-2 overexpression, and the fact that overexpression or antisense depletion of COX-2 failed to alter the level of p21(waf1/cip1) and p27(kip1) indicate the existence of a COX-2-independent mechanism in celecoxib-induced inhibition of cholangiocarcinoma cell growth.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14973068&dopt=Abstract celecoxib, Celebrex



celecoxib, Celebrex
Evaluation of the tocolytic effect of a selective cyclooxygenase-2 inhibitor in a mouse model of lipopolysaccharide-induced preterm delivery.

Sakai M, Tanebe K, Sasaki Y, Momma K, Yoneda S, Saito S.

Department of Obstetrics and Gynecology, Toyama Medical and Pharmaceutical University, 2630 Sugitani, Toyama-shi, Toyama, Japan.

The inflammatory process is known to cause preterm delivery. Recently, a cyclooxygenase (COX)-2 inhibitor has been developed as an anti-inflammatory drug with few side-effects. We evaluated the COX-2 inhibitor, Celecoxib, for its tocolytic effects and side-effects on dams and pups using a lipopolysaccharide (LPS)-induced preterm delivery mouse model (preterm delivery rates; 95%). With administration of Celecoxib (50, 10, 1 and 0.3 mg/kg), the preterm labour rate was significantly reduced to 18, 30, 36 and 60% respectively. The prostaglandin F(2alpha)(PGF(2alpha)) and PGE(2) concentrations in murine uterine tissue 4 and 10 h after LPS treatment with Celecoxib (10 and 1 mg/kg) were significantly lower than those in the LPS-treated group without CELECOXIB: With administration of 10 or 100 mg/kg Celecoxib, the fetal ductus arteriosus was constricted significantly in preterm and near-term rats, although constriction rates in preterm rats were significantly lower than those in near-term rats. Reproductive and renal functions in offspring whose mothers were treated with LPS and Celecoxib were normal. These data demonstrate that Celecoxib could be used as a new therapy for preterm labour. However, careful attention to constriction of the fetal ductus arteriosus should be given.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11385116&dopt=Abstract celecoxib, Celebrex