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Variability of the drug response to nonsteroidal anti-inflammatory drugs according to cyclooxygenase-2 genetic polymorphism

Authors Lee SJ, Park MK, Shin DS, Chun MH

Received 12 June 2017

Accepted for publication 8 August 2017

Published 13 September 2017 Volume 2017:11 Pages 2727—2736

DOI https://doi.org/10.2147/DDDT.S143807

Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Amy Norman

Peer reviewer comments 2

Editor who approved publication: Dr Qiongyu Guo

Sook Joung Lee,1,* Min Kyu Park,2,* Dong-Seong Shin,3 Min Ho Chun4

1Department of Physical Medicine and Rehabilitation, Dong-A University College of Medicine, Dong-A University Hospital, 2Department of Pharmacology and Clinical Pharmacology, Dong-A University College of Medicine, Dong-A University Hospital, Busan, 3Clinical Trials Center, Gachon University Gil Medical Center, Incheon, 4Department of Rehabilitation Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea

*These authors contributed equally to this work

Purpose: 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).
Patients and methods: 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.
Results: 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.
Conclusion: 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.

Keywords:
nonsteroidal anti-inflammatory agent, cyclooxygenase-2, single-nucleotide polymorphism, drug response, pharmacodynamics, clinical trial

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