OBJECTIVE: Our objective was to assess the role of the reportedly functional PTGS2 (prostaglandin-endoperoxide synthase 2/cyclooxygenase [COX] 2) promoter mutation -765G>C for the COX-2-inhibiting effects of celecoxib. METHODS: Twenty healthy carriers of the -765GG genotype and -765CC genotype (n = 10 each) received 200 mg of celecoxib orally. Blood samples were drawn at baseline and at 1, 3, 6, 9, and 24 hours after administration. Plasma concentrations of celecoxib and concentrations of prostaglandin E(2) (PGE(2)) produced by peripheral blood monocytes stimulated ex vivo with bacterial lipopolysaccharide (LPS) were analyzed by liquid chromatography-tandem mass spectrometry. Expression of COX-2 messenger ribonucleic acid and protein expression with and without LPS stimulation were analyzed by real-time polymerase chain reaction and Western blotting, respectively. RESULTS: LPS induced PGE(2) production (P < .001), and celecoxib reduced PGE(2) production from 19.3 +/- 7.2 ng/mL at baseline to 7.4 +/- 4.8 ng/mL at 1 hour (P < .001). The effect of celecoxib lasted for 9 hours (repeated-measures ANOVA, P <or= .001). Celecoxib inhibited PGE(2) production at a potency (ie, 50% effective concentration [EC(50)]) of 155.1 ng/mL (95% confidence interval, 101.6-208.5 ng/mL) in the homozygous carriers of the PTGS2 wild-type -765G allele and at a potency (EC(50)) of 186.6 ng/mL (95% confidence interval, 142.6-230.5 ng/mL) in the homozygous carriers of the PTGS2 variant -765C allele, which was not statistically significantly different (P = .36). Baseline PGE(2) concentrations, minimum baseline PGE(2) concentrations, and areas under the PGE(2) concentration versus time curve also did not differ between PTGS2 genotypes (P > .28). LPS up-regulated COX-2 messenger ribonucleic acid expression (P = .016) but was independent of genotype (P = .36). COX-2 protein expression was similar for both -765G>C genotypes (P = .63). CONCLUSION: The PTGS2 -765G>C single-nucleotide polymorphism does not modulate COX-2 inhibitory effects of celecoxib as assessed by an ex vivo whole blood assay. Thus the results indicate the need for further investigation toward PTGS2 pharmacogenetics-based prescription of celecoxib.
OBJECTIVE: Our objective was to assess the role of the reportedly functional PTGS2 (prostaglandin-endoperoxide synthase 2/cyclooxygenase [COX] 2) promoter mutation -765G>C for the COX-2-inhibiting effects of celecoxib. METHODS: Twenty healthy carriers of the -765GG genotype and -765CC genotype (n = 10 each) received 200 mg of celecoxib orally. Blood samples were drawn at baseline and at 1, 3, 6, 9, and 24 hours after administration. Plasma concentrations of celecoxib and concentrations of prostaglandin E(2) (PGE(2)) produced by peripheral blood monocytes stimulated ex vivo with bacterial lipopolysaccharide (LPS) were analyzed by liquid chromatography-tandem mass spectrometry. Expression of COX-2 messenger ribonucleic acid and protein expression with and without LPS stimulation were analyzed by real-time polymerase chain reaction and Western blotting, respectively. RESULTS:LPS induced PGE(2) production (P < .001), and celecoxib reduced PGE(2) production from 19.3 +/- 7.2 ng/mL at baseline to 7.4 +/- 4.8 ng/mL at 1 hour (P < .001). The effect of celecoxib lasted for 9 hours (repeated-measures ANOVA, P <or= .001). Celecoxib inhibited PGE(2) production at a potency (ie, 50% effective concentration [EC(50)]) of 155.1 ng/mL (95% confidence interval, 101.6-208.5 ng/mL) in the homozygous carriers of the PTGS2 wild-type -765G allele and at a potency (EC(50)) of 186.6 ng/mL (95% confidence interval, 142.6-230.5 ng/mL) in the homozygous carriers of the PTGS2 variant -765C allele, which was not statistically significantly different (P = .36). Baseline PGE(2) concentrations, minimum baseline PGE(2) concentrations, and areas under the PGE(2) concentration versus time curve also did not differ between PTGS2 genotypes (P > .28). LPS up-regulated COX-2 messenger ribonucleic acid expression (P = .016) but was independent of genotype (P = .36). COX-2 protein expression was similar for both -765G>C genotypes (P = .63). CONCLUSION: The PTGS2 -765G>C single-nucleotide polymorphism does not modulate COX-2 inhibitory effects of celecoxib as assessed by an ex vivo whole blood assay. Thus the results indicate the need for further investigation toward PTGS2 pharmacogenetics-based prescription of celecoxib.
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