Skarke Carsten, Reus Maximilian, Schmidt Ronald, Grundei Inga, Schuss Patrick, Geisslinger Gerd, Lötsch Jörn
Pharmazentrum Frankfurt/ZAFES, Institute of Clinical Pharmacology, Johann Wolfgang Goethe-University, Frankfurt, Germany.
Clin Pharmacol Ther. 2006 Dec;80(6):621-32. doi: 10.1016/j.clpt.2006.08.021.
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.
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.
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).
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.
我们的目的是评估据报道具有功能的PTGS2（前列腺素内过氧化物合酶2/环氧化酶[COX]2）启动子突变-765G>C对塞来昔布COX-2抑制作用的影响。
20名-765GG基因型和-765CC基因型的健康携带者（各10名）口服200mg塞来昔布。在基线以及给药后1、3、6、9和24小时采集血样。通过液相色谱-串联质谱法分析塞来昔布的血浆浓度以及用细菌脂多糖（LPS）体外刺激外周血单核细胞产生的前列腺素E2（PGE2）浓度。分别通过实时聚合酶链反应和蛋白质免疫印迹法分析有无LPS刺激时COX-2信使核糖核酸的表达和蛋白质表达。
LPS诱导PGE2产生（P<.001），塞来昔布使PGE2产生从基线时的19.3±7.2ng/mL降至1小时时的7.4±4.8ng/mL（P<.001）。塞来昔布的作用持续9小时（重复测量方差分析，P≤.001）。在PTGS2野生型-765G等位基因纯合携带者中，塞来昔布抑制PGE2产生的效价（即50%有效浓度[EC50]）为155.1ng/mL（95%置信区间，101.6-208.5ng/mL），在PTGS2变异型-765C等位基因纯合携带者中，效价（EC50）为186.6ng/mL（95%置信区间，142.6-230.5ng/mL），两者无统计学显著差异（P=.36）。PTGS2基因型之间的基线PGE2浓度、最低基线PGE2浓度以及PGE2浓度-时间曲线下面积也无差异（P>.28）。LPS上调COX-2信使核糖核酸表达（P=.016），但与基因型无关（P=.36）。两种-765G>C基因型的COX-2蛋白表达相似（P=.63）。
通过体外全血试验评估，PTGS2 -765G>C单核苷酸多态性不调节塞来昔布的COX-2抑制作用。因此，结果表明需要对基于PTGS2药物遗传学的塞来昔布处方进行进一步研究。
