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Home , Antiplatelet drug, CYP2C9, Fenoprofen, Ketorolac, Lumiracoxib, Oxaprozin

The 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

JE Wyatt1, WL Pettit1 and S Harirforoosh2

With the beginning of the 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 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 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;

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 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 , anti-inflammatory and 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 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 the codes for, most importantly rate and .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 possess a minimum of one single- nomics of NSAIDs in order to best treat patients with the most 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 . For instance, the metabolism of Genetic variations can cause a wide range of variability in several NSAIDs (for example, , and ) pharmacokinetic profile of drugs, resulting in differences in efficacy depends on CYP2C9.15 This 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 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 will be a valid pharmacotherapeutic option for a commonly prescribed , 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- .9 NSAIDs inhibit the ability of cyclooxygenase tions.20 This could subsequently aid a physician’s or prescriber’s (COX) to produce prostaglandins from , 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 (‘’) 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 CYP2C9*3/*3 and the wild type (CYP2C9*1/*1) for patients Salicylate salts receiving celecoxib 200 mg twice daily for 15 days. This study assessed samples using high-performance liquid chromato- 28 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 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 derivatives shift from one enzymatic pathway to another that might become calcium saturated leading to the compromising mechanism failing to Flubiprofen sodium Ibuprofen maintain an adequate level of drug elimination. However, it is still patient specific as to whether this would be consistent with greater , 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 effects.29 Chan et al.30 reported the efficacy and safety of low (200 mg, twice daily) and high (400 mg, twice daily) doses of 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 variant and who received low or high doses of celecoxib as tromethamine compared with patients who received . 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 were observed in wild-type genotyped subjects who received low , oxaprozin potassium or high dose of celecoxib, the events were reported only in variant genotyped subjects who were administered high doses of the 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 for relief of the acute pain 26 associated with dental pain after extraction as well as dose- of celecoxib. dependent relief from the inflammation accompanying rheuma- Celecoxib exerts its effect by inhibition of COX-2, which is toid and .3 encoded by the prostaglandinendoperoxide synthase 2/COX-2 (PTGS2) gene. In a small study of 20 healthy individuals, Skarke et al.31 examined the effect of a SNP (_765G_C) in the PTGS2 gene Celecoxib on the inhibitory effect of celecoxib or the expression of COX-2 Celecoxib’s indications conferred by the Food and Drug Admin- enzyme. The participants included carriers of the wild-type allele istration (FDA) include the treatment of acute pain, osteoarthritis, (_765GG) and variant allele (_765CC) and received a single dose of and .22 Celecoxib is celecoxib (200 mg). The investigators did not find any significant metabolized via CYP2C9 (estimated at 72–92%).23 In addition, difference in terms of COX-2 expression and inhibitory effect celecoxib is an inhibitor of CYP2D6. A study conducted by Werner between wild-type and variant genotype groups. et al. compared the effect of celecoxib and in the metabolism of metoprolol, a of CYP2D6. The study enrolled 12 healthy male subjects; there was a more than 40% Lumiracoxib increase in the area under the curve (AUC) plasma concentration Lumiracoxib is approved in multiple countries outside the United of metoprolol when used concomitantly with celecoxib as States and was deemed ‘not approvable’ by the FDA because of compared with rofecoxib.24 toxicity concerns.32 This COX-2 inhibitor was developed for As stated earlier, celecoxib is extensively metabolized by the treatment of osteoarthritis and acute pain. The trial utilized for CYP2C9.25 An in vitro study utilizing human liver microsomes in the approval process was the Therapeutic Arthritis Research addition to yeast microsomes expressing a number of CYP and Gastrointestinal Events Trial (TARGET).33,34 This trial enrolled polymorphisms showed that CYP2C9*3 had a lower intrinsic more than 18 000 subjects Z50 years of age who suffered from clearance of celecoxib when compared with the wild-type osteoarthritis. An independent case–control genome-wide asso- CYP2C9*1 samples.26 There are conflicting results about whether ciation trial was conducted utilizing the patients from the TARGET CYP2C9*2 has a significant decrease in intrinsic clearance.26,27 trial. It was a retrospective analysis utilizing a genome scan on 41 The most marked decrease in metabolism of celecoxib was lumiracoxib-treated subjects with liver injury and 176 lumiracoxib- noted in enzymes expressing homozygous polymorphism treated control subjects.32 The analysis revealed a large number of CYP2C9*3/*3.26,27 A corresponding increase in celecoxib’s AUC SNPs from 6, showing an association with rs9270986

& 2012 Macmillan Publishers Limited The Pharmacogenomics Journal (2012), 462 – 467 Pharmacogenetics of NSAIDs JE Wyatt et al 464 as the SNP with the lowest P-value (P ¼ 2.8 Â 10 À 10). A total of Indomethacin seven SNPs, exclusively mapped to the major histocompatability Indomethacin can be used for closure of patent complex (MHC) class II region, maintained statistical significance in premature infants.22 Indomethacin is metabolized by CYP2C9 following genome-wide multiple-testing correction. Furthermore, and carboxy esterase (minor pathway).19 One study assessed the these SNPs possessed association with lumiracoxib-related liver clearance of indomethacin and observed the role of CYP2C9 and enzyme elevation from the TARGET trial. The study was able to CYP2C19, and noted that there was a 16-fold higher difference reproduce the MHC class II region results utilizing 98 lumiracoxib- when assessing the role of CYP2C9 in comparison with that of treated cases and 405 matched lumiracoxib-treated controls. CYP2C19 when clearing this NSAID.39 Researchers have assessed Interestingly, the HLA-DQA1*0102 allele’s sensitivity improved the role of CYP2C9 in the overall clearance of indomethacin and coinciding with the liver enzyme elevation thresholds. These cor- have determined that its role is substantial regarding the responding events help highlight the importance of pharma- clearance of indomethacin.40 There was no significant difference cogenetic utilization with some pharmacotherapeutic options. in the AUC for indomethacin in patients experiencing gastro- intestinal bleeding compared with those without bleeding.41 An additional study assessed the frequency of the CYP2C9 variation SALICYLATES among 20 þ individuals with a past medical history of NSAID- related gastric ulceration versus 30 þ individuals who did not Acetylsalicylic acid have a history of gastropathy.42 The ensuing frequency of Acetylsalicylic acid (aspirin) is rapidly hydrolyzed to , CYP2C9*1/*1 (wild-type) genotype was similar to that possessed and exerts anti-inflammatory effects by irreversibly inhibiting both 35 by subjects with a history of gastric ulcers associated with NSAID isoforms of COX, COX-1 and COX-2. COX-1 is the predominate use and those receiving NSAIDs without the gastric ulceration. form of the COX enzyme found in , and patients Additionally, the two other genotypes identified in the small study with the COX-1 G allele A842G polymorphism have shown a were both heterozygous genotypes, CYP2C9*1/*2 and CYP2C9*1/*3. decreased response to aspirin, together with patients demon- There was no statistically significant difference between either of strating C13254T polymorphism of the GP VI , a the two groups, which would weaken the case for a phar- receptor responsible for subsequent activation of platelets in the 36 macogenetics difference accounting for the past medical history clotting cascade. Aspirin prompts a lifespan defect in platelets; of gastrointestinal ulcerations. It was determined that there were this is clinically detectable as a prolongation of the bleeding time no homozygous genotypes (CYP2C9*2/*2 and CYP2C9*3/*3) for patients receiving aspirin. This effect appears to be principally 3,37 identified in this study, and this may limit the applicability of related to the permanent inactivation of COX. Of the two the study to the NSAID-taking population as a whole because isoenzymes of COX, type 1 is constitutively expressed in most of the inexhaustive patient population. Thus, based upon the tissues and is involved in the synthesis of the prostaglandins and evidence available, pharmacogenetic testing for indomethacin A2. would not be as clinically useful as other NSAIDs (for example, Patients possessing polymorphisms may not experience the lumiracoxib) because of lack of relationship between CYP2C9 expected therapeutic effect upon receiving aspirin. This might variants and adverse events. precipitate the patient requiring more aspirin than is typically utilized, resulting in an increased propensity for renal and gastrointestinal adverse effects. A small cross-sectional study PROPIONIC ACID DERIVATIVES observed a faster in vivo conjugation of salicylic acid in patients 38 Propionic acid derivatives are COX nonselective inhibitors. Propionic genotyped UGT1A6*2/*2 than in the wild-type UGT1A6*1/*1. The acid derivatives enjoy approvals for rheumatoid and osteoarthritis, faster conjugation may subsequently influence the therapeutic in addition to pain, and primary .3 response to aspirin; however, the study was limited by its design and small number of participants, and more study designs with larger populations should be conducted to make a more Flurbiprofen is an organic acid43 that is metabolized by CYP2C9 definitive conclusion. Clinically speaking, with the low cost of 0 18 various aspirin products and the relative high cost of pharma- forming 4 -hydroxiflurbiprofen. Interestingly, flurbiprofen is a medication that is used in the assessment of CYP2C9 variations cogenetic testing, applicability of testing would not be applicable 43 for most patients. and pharmacokinetic ramifications. A typical hyperbolic profile metabolism is displayed for CYP2C9*3 and CYP2C9*5, in addition to the wild-type CYP2C9*1. CYP2C9*3 and CYP2C9*5 alleles showed a diminished formation of 40hydroxiflurbiprofen, higher ACETIC ACID DERIVATIVES Michaelis–Menten constant (Km) and lower maximum velocity The acetic acid derivatives possess higher potency than that of (Vmax), with CYP2C9*5 having a more pronounced difference 18 aspirin.3 when compared with CYP2C9*1. A 2003 study assessed the effect of the variation of CYP2C9*1/*1 versus *1/*2 versus *1/*3 for flurbiprofen. The results showed that the AUC was higher with a Diclofenac simultaneous decrease in clearance for the CYP2C9*1/*3 group 44 Diclofenac’s foremost route of metabolism uses CYP2C9 forming compared with the CYP2C9*1/*1 group. A pharmacokinetic study 4’-hydroxidiclofenac.16 Various CYP2C9 polymorphisms have been published in 2011 was performed in 22 male Pakistanis that studied to determine whether they possess a negative effect further justifies that more data are required for the elucidation of on diclofenac’s pharmacokinetics resulting in increased toxicities. pharmacogenetics role for this medication. This study showed a To date, studies have shown that different CYP2C9 alleles do not difference in metabolism of flurbiprofen for one of the subjects in comparison with the other 21 male subjects, hinting at an seem to elicit a clinically significant effect of the pharmacokinetic 45 parameters or hepatic toxicity correlated with the metabolism interindividual basis for this difference. of diclofenac.16,17,28 In addition to the pharmacogenetics of diclo- fenac, it has been theorized that this NSAID binds differently to the Ibuprofen CYP2C9 enzyme irrespective of the pharmacogenetics variation Ibuprofen undergoes extensive hepatic metabolism, mainly into possessed by a patient. This may affect some of the pharma- either hydroxylate or carboxylate derivatives.3 Ibuprofen is a cokinetic data that have been gathered for diclofenac.18 nonselective inhibitor of COX-1 and COX-2. Many commercially

The Pharmacogenomics Journal (2012), 462 – 467 & 2012 Macmillan Publishers Limited Pharmacogenetics of NSAIDs JE Wyatt et al 465 available formulations include a of R-( À ) and role of CYP2C9 in the overall clearance of naproxen and concluded S-( þ ). Following administration of racemic ibuprofen, B60% of that CYP2C9 played a minor role in naproxen clearance, suggesting the R-( À ) enantiomer is converted to the S-( þ ) enantiomer, that pharmacogenetic differences would not be clinically significant the more potent inhibitor of COX-1 and COX-2.46,47 Data from if compromised CYP2C9 activity was possessed by a patient taking previous biochemical studies indicate that CYP2C8 and CYP2C9 this medication.40 Furthermore, there was no significant difference may be the S-ibuprofen , in contrast to R-ibuprofen between the Cmax and AUC for naproxen in patients experiencing being primarily metabolized by CYP2C8.48,49 gastrointestinal bleeding compared with those without bleeding There are at least three clinically relevant alleles of CYP2C9 in from two studies.41,42 The subsequent frequency of CYP2C9 Caucasian populations, and each allele confers different activity.50 genotype was comparable to that of subjects with a history of The wild-type allele, also known as CYP2C9*1, possesses an arginine gastric ulcers associated with NSAID use and those receiving at codon 144 and an isoleucine at codon 359. The CYP2C9*2 NSAIDs minus the gastric ulceration.41,42 variant substitutes a cysteine in lieu of arginine at codon 144. The CYP2C9*3 variant contains in lieu of isoleucine at codon 359.50 Ibuprofen-facilitated inhibition of the COX-1 and COX-2 is ENOLIC ACIDS influenced by the CYP2C9 genotype. Compromised clearance of Enolic acids inhibit COX-1 and COX-2 while also possessing anti- racemic mixture ibuprofen in addition to (S)-ibuprofen were exper- inflammatory and action. The enolic acids hold efficacy ienced by carriers of the two CYP2C9*3 alleles. Applying this that is similar to aspirin, indomethacin or naproxen for two pharmacokinetic knowledge to the clinical setting may influence specific disease states, rheumatoid arthritis and osteoarthritis.3 clinicians to anticipate an increase in the pharmacodynamic potential of ibuprofen in patients possessing those specific Piroxicam variants.50 According to in vitro data and pharmacokinetic The drug is primarily metabolized by CYP2C9.19 Although a studies, the activity provided by CYP2C9*2 is slightly less than substrate inhibition metabolism is reported for CYP2C9*1 and the activity of the wild-type allele.51 However, CYP2C9*3 confers CYP2C9*3, the CYP2C9*5 metabolism profile was hyperbolic. As the roughly 10 to 30% of the enzymatic activity of the wild type, result, the investigators concluded that a single change in amino depending on the substrate being studied.51–54 Genomic factors acid was correlated to a significant change in metabolism of play a role in the extent to which ibuprofen is eliminated from the piroxicam.18 body. A study published in 2004 comparing the role of CYP2C8 and CYP2C9 polymorphisms in pharmacokinetic profile of ibuprofen noted a significant difference in the clearance of ibuprofen when Tenoxicam comparing CYP2C8*1/*1 (4.04 l h À 1)withCYP2C8*3/*3 (0.40 l h À 1). Tenoxicam is primarily metabolized by CYP2C9.58 The in vivo This ibuprofen elimination difference was also noted in CYP2C9*1/*1 clearance of tenoxicam for the CYP2C9 Ile359 to Leu359 (4.43 l h À 1) versus CYP2C9*3/*3 (1.13 l h À 1).55 variant allele represents o10% of that of the wild-type allele.59 There was a similar effect of ibuprofen for the CYP2C9 Vianna-Jorge et al.58 studied the frequency of CYP2C9*1, CYP2C9*2 polymorphism, especially pertaining to the inhibition of COX-1. and CYP2C9*3 among Brazilians and their influence on the Pharmacodynamic activity was assessed using ex vivo thrombox- pharmacokinetics of tenoxicam (20 mg). They reported a similar ane B2 formation. The authors concluded that diminished S-( þ ) frequency of the examined alleles in Brazilian population compared enantiomer clearance and increased pharmacodynamic activity with that of Caucasians. Also, minimum concentration, maximum may affect patients receiving ibuprofen.50 An additional concentration and AUC values were higher in the subjects ramification of decreased activity of the CYP2C9*2 and CYP2C9*3 genotyped CYP2C9*1/*3 as compared with those of CYP2C9*1/*1 alleles can include an increase in the concentrations of NSAIDs in after repeated doses of tenoxicam. Concerning the influence of the patients, inadvertently manifesting itself as an acute upper CYP2C9*3 allele on the pharmacokinetics of tenoxicam, the result of gastrointestinal bleeding.56 This understanding helped initiate a this study was in line with the results of another study conducted to prospective study seeking to determine whether the frequency of examine the influence of CYP2C9 and CYP2C8 alleles on tenoxicam the CYP2C9*3 allele would be overrepresented among patients pharmacokinetics.60 In the latter study, the investigators established treated with non-aspirin NSAIDs in comparison with the frequency a link between the presence of CYP2C9*3 and a change in of the CYP2C9*3 allele for patients on aspirin would be com- pharmacokinetic parameters. Altogether, the data support the fact parable to the general population’s frequency.57 The non-aspirin that the pharmacokinetics of tenoxicam is related to the genotype NSAID group, in addition to ibuprofen, included ketoprofen, of the individuals taking the drug. diclofenac, piroxicam, meloxicam, tenoxicam and rofecoxib. To assist in the determination of an odds ratio for acute upper gastrointestinal bleeding, the investigators analyzed patients with PERSPECTIVES NSAID-related acute upper gastrointestinal bleeding. Aspirin was A considerable amount of data have already been collected not appreciably metabolized by CYP2C9, whereas non-aspirin concerning the pharmacogenetics of the main metabolic path- NSAIDs are to differing degrees metabolized by CYP2C9. Based ways and the major metabolites synthesized for NSAIDs. This, upon the data collected, the hypothesis concerning the fre- however, is not the case for secondary metabolic pathways quencies was justified. The frequency of the CYP2C9*3 allele and the minor metabolites. The data are very limited and these was 3.7 times greater in the non-aspirin group than in the secondary pathways may seem superficially important; however, aspirin group (odds ratio 5, 95% confidence interval 2.2–11.1, this information may be applicable to individuals who are P ¼ 0.0001).57 deficient in or have impairment of the metabolizing enzymes for NSAIDs. For example, diclofenac’s primary enzyme is CYP2C9, whereas UGT2B7 and a variety of other CYP enzymes are res- Naproxen ponsible for the secondary metabolism.19 Additionally, it has been Naproxen is indicated for juvenile and rheumatoid arthritis, osteo- shown that the presence of CYP2C8 variant alleles can cause arthritis, tendonitis and acute gouty attacks.22 Naproxen sodium diclofenac-induced hepatotoxicity61 in addition to acute gastro- is metabolized by the liver enzyme CYP2C9 forming 6- intestinal bleeding after the use of NSAIDs.62 desmethylnaproxen.25 Like flurbiprofen, the CYP2C9*3 and It is worth noting that in addition to polymorphisms in CYP2C9*5 alleles show a lower clearance when compared with metabolizing enzymes, there are additional genetic factors that the wild-type CYP2C9*1.18 However, another study assessed the may contribute to variable drug response among patients. For

& 2012 Macmillan Publishers Limited The Pharmacogenomics Journal (2012), 462 – 467 Pharmacogenetics of NSAIDs JE Wyatt et al 466 instance, in a study assessing acute pain and variation in res- for pharmacogenetic determinations of adverse effects that ponses to NSAIDs, researchers examined the level patients might experience, and adjusting the dose based on the of the genes encoding enzymes related to production of COX-1 patient’s genotype or choosing other NSAIDs that do not share and COX-2 (PTGS1 and PTGS2, respectively) in addition to the the same propensity for accumulation. In conclusion, pharma- genetic polymorphisms and analgesic response to a nonselective cogenetics is just one tool that should be employed to continue NSAID (ibuprofen) or a COX-2-selective inhibitor (rofecoxib) the improvement of patient care by providing analgesia or following minor surgery.63 This study confirmed the wide heter- minimization of pain while avoiding serious side effects such as ogeneity of gene expression of PTGS1 and PTGS2 among renal, cardiovascular and gastrointestinal effects. individuals. The COX-1 expression in these patients is marginally diminished, an B36% decrease from baseline values, whereas COX-2 expression was significantly amplified, an B300% increase from baseline values 2–4 h after surgery. The levels of both CONFLICT OF INTEREST enzymes returned to baseline values at 48 h after surgery. The The authors declare no conflict of interest. effect of ibuprofen or rofecoxib administration on gene expression values at 48 h after minor surgery was an inconsequential detectable change in PTGS1 expression and increased PTGS2 REFERENCES expression. However, the response to analgesic effect of ibuprofen and rofecoxib was opposite and genotype related at 48 h after 1 Palmer SN, Giesecke NM, Body SC, Shernan SK, Fox AA, Collard CD. Pharmaco- surgery. The subjects identified as homozygous GG for PTGS2 genetics of and analgesic agents. Anesthesiology 2005; 102: 663–671. 2 Ma Q, Lu AY. Pharmacogenetics, pharmacogenomics, and individualized medi- SNP2 demonstrated a better response to analgesic effect of cine. Pharmacol Rev 2011; 63: 437–459. rofecoxib compared with ibuprofen administration. In contrast, 3 Goodman LS, Brunton LL, Chabner B, Knollmann BC. Goodman & Gilman’s response to ibuprofen was more evident in subjects identified as pharmacological basis of therapeutics, 12th edn. 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Expert Opin Drug Metab Toxicol 2009; there appears to be a considerable amount of research, such as 5: 607–620. retrospective studies modeled after Singer et al.,32 that must be 20 Lee CR, Goldstein JA, Pieper JA. 2C9 polymorphisms: a compre- hensive review of the in-vitro and human data. Pharmacogenetics 2002; 12:251–263. completed to fully understand and ascertain the full mechanism of 21 Liao JK. Safety and efficacy of statins in Asians. Am J Cardiol 2007; 99: 410–414. elimination that is employed when speaking of NSAIDs. These 22 American Society of Hospital Pharmacists. AHFS Drug Information. Published by types of studies would help identify associations between genetic authority of the Board of Directors of the American Society of Health-System markers and adverse effects for patients. This would further allow Pharmacists: Bethesda, MD, 2009.

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