The Pharmacogenomics Journal (2012) 12, 462–467 & 2012 Macmillan Publishers Limited All rights reserved 1470-269X/12 www.nature.com/tpj REVIEW Pharmacogenetics of nonsteroidal anti-inflammatory drugs JE Wyatt1, WL Pettit1 and S Harirforoosh2 With the beginning of the Human Genome Project, an emerging field of science was brought to the forefront of the pharmaceutical community. Pharmacogenetics facilitates optimization of the current patient-centered care model and pharmacotherapy as a whole. Utilizing these ever-expanding branches of science to nonsteroidal anti-inflammatory drugs (NSAIDs) can provide novel opportunities to affect patient care. With a wide range of NSAID choices available as treatment options for relieving pain and/or reducing inflammation or fever, a more systematic way of selecting the ideal agent for the patients based upon their genetic information could spare them from a potentially permanent health-care condition. Furthermore, if a patient possesses or lacks certain alleles, serious adverse events can be anticipated and avoided. The tailoring of drug therapy can be achieved using the published data and cutting-edge genetic testing to attain a higher standard of care for patients. The Pharmacogenomics Journal (2012) 12, 462–467; doi:10.1038/tpj.2012.40; published online 9 October 2012 Keywords: NSAIDs; pharmacogenetics; polymorphism; cyclooxygenase INTRODUCTION throughout the body and COX-2 is expressed in response to 11 Pharmacogenetics is the study of the genetic factors influencing injury or inflammation. NSAIDs are divided into two broad variation in drug metabolism and response.1 The completion of categories based on their selectivity for COX: nonselective the human genome project facilitated the study of variable drug NSAIDs and COX-2-selective inhibitors. NSAIDs are indicated as effects based on individual genetic make-up.2 The human genome analgesics, anti-inflammatory and antipyretic agents in numerous project has identified numerous types of genetic variations among conditions. individuals that may or may not alter drugs effects. The genetic The commonplace side effects that are manifested in patients variations are either classified as polymorphisms or mutations.3 A receiving NSAIDs can include gastrointestinal tract ramifications. polymorphism is defined as variation in a DNA sequence that The gastrointestinal side effects can range from stomach upset to occurs at a frequency of at least 1% in the human population, fatal-diaphragm-like colonic strictures.12 Other side effects of whereas a mutation occurs in o1%. There are many factors NSAIDs include renal abnormalities such as hyperkalemia, acute influencing whether or not a polymorphism will result in a change renal failure, hypernatremia, compromised glomerular filtration in function of the protein the gene codes for, most importantly rate and edema.13,14 being the region of the gene the polymorphism occurs on.4 More It is crucial to understand the pharmacogenetics/pharmacoge- than 90% of human genes possess a minimum of one single- nomics of NSAIDs in order to best treat patients with the most nucleotide polymorphism (SNP), and the vast majority of every appropriate agents that will have enhanced therapeutic outcomes human gene is marked by a sequence variation. More than 14 with fewer side effects. Although not all NSAIDs would realistically million SNPs have currently been identified from the human benefit from pharmacogenetic testing, several NSAIDs demonstrate genome. More than 60 000 SNPs have been located in the coding variable drug response based upon various genetic polymorph- regions of the genes.5 isms of metabolizing enzymes. For instance, the metabolism of Genetic variations can cause a wide range of variability in several NSAIDs (for example, celecoxib, diclofenac and ibuprofen) pharmacokinetic profile of drugs, resulting in differences in efficacy depends on CYP2C9.15 This enzyme can have heterozygous and toxicity profiles of pharmaceuticals. This can be due to genetic and homozygous variant genotypes, such as CYP2C9*2/*2 and differences in the proteins involved in drug elimination or drug CYP2C9*1/*3. CYP2C9*2 and CYP2C9*3, two of the more common targets. Pharmacogenetics allows for optimization of pharma- variant alleles, have been extensively studied.16–19 Genetic testing cotherapy based upon the patient’s respective genetic make-up.6 for these specific variances in alleles would aid in determining if a Nonsteroidal anti-inflammatory drugs (NSAIDs) (Table 1) are the medication will be a valid pharmacotherapeutic option for a commonly prescribed medications, with an estimated 70 million specific patient. For example, there appears to be a demarcation in number of prescriptions annually written and $6.8 billion spent the enzymatic function because of the fact that *1*1 genotype worldwide in the attainment of this drug class.7,8 The therapeutic exists in 96% of the Chinese and Japanese populations, whereas and sides effect of NSAIDs are caused by decreased production of heterozygous CYP2C9*1/*3 boasts 4% of these two popula- prostaglandins.9 NSAIDs inhibit the ability of cyclooxygenase tions.20 This could subsequently aid a physician’s or prescriber’s (COX) to produce prostaglandins from arachidonic acid, sub- choice of a drug therapy regimen that can increase efficacy while sequently leading to a decreased amount of inflammation simultaneously decreasing adverse effects, similar to the concern experienced by most patients. Currently, there are two identified of certain HMG-CoA (3-hydroxy-3-methylglutaryl-coenzyme A) isoforms of COX.10 COX-1 is constitutively present in many tissues reductase inhibitors (‘statins’) in Asians.21 This article discusses 1Gatton College of Pharmacy, East Tennessee State University, Johnson City, TN, USA and 2Department of Pharmaceutical Sciences, Gatton College of Pharmacy, East Tennessee State University, Johnson City, TN, USA. Correspondence: Dr S Harirforoosh, Department of Pharmaceutical Sciences, Gatton College of Pharmacy, East Tennessee State University P.O. Box 70594, Johnson City, TN 37614-1708, USA. E-mail: [email protected] Received 3 January 2012; revised 15 May 2012; accepted 5 September 2012; published online 9 October 2012 Pharmacogenetics of NSAIDs JE Wyatt et al 463 Table 1. Nonsteroidal anti-inflammatory agents3,22 would be expected in individuals expressing CYP2C9*3 allele, and this could result in an increase in dose-related adverse reactions Diaryl heterocyclic COX-2 selective inhibitors due to accumulation of celecoxib. Celecoxib However, these results are inconsistent with another small group study of nonsmoking Caucasians of both sexes that failed to find a Salicylates clinically significant difference between the homozygous Aspirin CYP2C9*3/*3 and the wild type (CYP2C9*1/*1) for patients Salicylate salts Salsalate receiving celecoxib 200 mg twice daily for 15 days. This study assessed blood samples using high-performance liquid chromato- 28 Acetic acid derivatives graphy. These conflicting results may be explained by the fact Diclofenac sodium, diclofenac potassium, diclofenac epolamine that celecoxib is also metabolized by CYP3A4; individuals with Lumiracoxib CYP2C9 polymorphisms may experience different pharmacokinetic Indomethacin profiles depending on their CYP2C9/CPY3A4 ratio.27 Furthermore, in addition to the ratio of enzymes, there might be a corrective Propionic acid derivatives shift from one enzymatic pathway to another that might become Fenoprofen calcium saturated leading to the compromising mechanism failing to Flubiprofen sodium Ibuprofen maintain an adequate level of drug elimination. However, it is still Ketoprofen patient specific as to whether this would be consistent with greater Naproxen, naproxen sodium efficacy or with an increased incidence and severity of the adverse events. These adverse events could include an increased Enolic acids propensity for renal impairment or other dose-related side Meloxicam effects.29 Chan et al.30 reported the efficacy and safety of low Piroxicam (200 mg, twice daily) and high (400 mg, twice daily) doses of Tenoxicam celecoxib in 1660 patients genotyped wild type, CYP2C9*2 or CYP2C9*3. A protective effect (a reduction in adenoma) of Other Diflunisal celecoxib was observed in subjects genotyped wild type or Etodolac variant and who received low or high doses of celecoxib as Ketorolac tromethamine compared with patients who received placebo. But, an additional Meclofenamate sodium benefit of high dose was demonstrated only in the subjects with Mefanamic acid CYP2C9*3 genotype. Although the cardiovascular adverse events Nabumetone were observed in wild-type genotyped subjects who received low Oxaprozin, oxaprozin potassium or high dose of celecoxib, the events were reported only in variant Sulindac genotyped subjects who were administered high doses of the Tolmetin sodium drug.30 A clinical study conducted by Tang et al.27 measured celecoxib concentrations in plasma samples after a single oral dose. major NSAIDs with relation to their known pharmaco- CYP2C9*1/*3 and CYP2C9*3/*3 genotypes demonstrated higher genetics and possible application for their clinical use. values of AUC compared with subjects with wild-type genotypes. There were lower concentrations of carboxy-celecoxib and hydroxyl-celecoxib in heterozygous and homozygous CYP2C9*3 29 DIARYL HETEROCYCLIC COX-2-SELECTIVE INHIBITORS allele carriers as well. These data help to support the hypothesis that CYP2C9 polymorphisms affect the variability in the COX-2-selective inhibitors can be used