Lee Sook Joung, Park Min Kyu, Shin Dong-Seong, Chun Min Ho
Department of Physical Medicine and Rehabilitation, Dong-A University College of Medicine, Dong-A University Hospital.
Department of Pharmacology and Clinical Pharmacology, Dong-A University College of Medicine, Dong-A University Hospital, Busan.
Drug Des Devel Ther. 2017 Sep 13;11:2727-2736. doi: 10.2147/DDDT.S143807. eCollection 2017.
Cyclooxygenase (COX) is the main pharmacodynamic target of nonsteroidal anti-inflammatory drugs (NSAIDs). We investigated the inhibitory effects on COX-2 after NSAIDs administration using a lipopolysaccharide (LPS)-derived COX-2 induction model in whole blood, according to the genotypes of COX-2 single-nucleotide polymorphisms (SNPs).
Seven genotypes of COX-2 SNPs were selected from public databases and analyzed in 324 healthy subjects. Two genotypes showing a high percentage of variability were selected. A clinical trial examining pharmacodynamics according to the genotype of two SNPs (rs5275 and rs689466) was conducted. Twenty subjects were administered a single oral dose of 200 mg of celecoxib, and pharmacokinetic and pharmacodynamic analyses were performed.
In the analysis of the pharmacokinetic parameters, significant differences in drug exposure were not investigated for each SNP genotype. The pharmacodynamic analysis revealed that the maximum effect of COX-2 inhibition was achieved at 2.0 hours for all genotypes of COX-2 SNPs after a single oral administration of 200 mg celecoxib. The inhibitory effects according to the genotype of COX-2 SNPs were investigated, and the area under the effect curve of the rs689466 GG genotype was significantly lower than that for the AA or AG genotype.
Our results demonstrated that inhibitory effects of celecoxib on COX-2 induction were different according to the genotype of COX-2 SNPs. In the present study, rs689466 is responsible for the variability of the response to celecoxib, suggesting that a subject with the GG genotype of rs689466 would be more responsive to celecoxib in terms of COX-2 inhibition.
环氧化酶（COX）是非甾体抗炎药（NSAIDs）的主要药效学靶点。我们根据COX-2单核苷酸多态性（SNP）的基因型，使用全血中脂多糖（LPS）诱导的COX-2诱导模型，研究了NSAIDs给药后对COX-2的抑制作用。
从公共数据库中选择7种COX-2 SNP基因型，并在324名健康受试者中进行分析。选择两种显示出高变异百分比的基因型。进行了一项根据两个SNP（rs5275和rs689466）基因型检查药效学的临床试验。20名受试者单次口服200 mg塞来昔布，并进行药代动力学和药效学分析。
在药代动力学参数分析中，未对每种SNP基因型的药物暴露差异进行研究。药效学分析显示，单次口服200 mg塞来昔布后，所有COX-2 SNP基因型在2.0小时时达到COX-2抑制的最大效应。研究了根据COX-2 SNP基因型的抑制作用，rs689466 GG基因型的效应曲线下面积显著低于AA或AG基因型。
我们的结果表明，塞来昔布对COX-2诱导的抑制作用因COX-2 SNP基因型而异。在本研究中，rs689466是导致对塞来昔布反应变异性的原因，这表明rs689466 GG基因型的受试者在COX-2抑制方面对塞来昔布的反应更强。
