Send Orders for Reprints to [email protected] 326 Current Drug Metabolism, 2014, 15, 326-343 Prediction by Pharmacogenetics of Safety and Efficacy of Non-Steroidal Anti- Inflammatory Drugs: A Review
Victoria Rollason1,*, Caroline Flora Samer1,2, Youssef Daali1,2 and Jules Alexandre Desmeules1,2
1Division of Clinical Pharmacology and Toxicology, Multidisciplinary Pain Centre, University Hospitals of Geneva and University of Geneva, Switzerland; 2Swiss Centre for Applied Human Toxicology (SCAHT), University of Geneva, Switzerland
Abstract: Non-steroidal anti-inflammatory drugs (NSAIDs) are the most frequently used drugs, either on prescription or over-the- counter (OTC). Their daily dosage is based on randomised controlled trials and an empirical clinical assessment of their efficacy and tox- icity that allows dose adjustment. The individual response can however be altered by environmental and genetic pharmacokinetic and pharmacodynamic factors. This review summarizes the available pharmacogenetic data that explains part of the variability in response and occurrence of adverse drug reactions to NSAIDs treatment, with a thorough focus on CYP2C9, uridine diphosphate glucuronosyl- transferases (UGTs) and cyclooxygenases (COX1 and COX2). Other polymorphisms that are currently being studied and could also ex- plain the interindividual variability in the efficacy and safety of NSAIDs will also be considered. Keywords: COX, CYP2C8, CYP2C9, genetic polymorphism, NSAIDs, PTGS, UDP glucuronsyltransferases, UGT.
INTRODUCTION efficacy and toxicity of NSAIDs have been reported for only some Non-steroidal anti-inflammatory drugs (NSAIDs) belong to the of these PK and PD steps. We will evaluate in this review the class of drugs most commonly taken by patients, either on prescrip- pharmacogenetic data available for NSAIDs and their potential tion or over-the-counter (OTC). Several studies have attempted to clinical consequences. estimate the utilisation of NSAIDs in the general population. In the METABOLISM: PHASE I ENZYMES United States, 70 million prescriptions for NSAIDs are issued and 30 billion OTC NSAIDs are sold per year [1]. One hundred and CYTOCHROME P450 2C9 (CYP2C9) forty seven million adults in the United States reported using an Cytochrome P450 2C9 (CYP2C9) represents nearly 20% of all NSAID every week, 9% on prescription and 76% as OTC drugs [2]. human hepatic cytochromes and metabolizes approximately 15% of A study conducted in 2002 in the United States showed that 83% of the drugs available on the market (more than a hundred) [5]. respondents had used OTC analgesics during the past year, 29% CYP2C9 is highly polymorphic and 34 allelic variants and several weekly and 15% daily. The two most commonly used OTC analge- subvariants have been characterized since 1994 [6]. Moreover, in sics were ibuprofen and paracetamol (33% of consumers for each 2013, 22 new variants were identified, 21 in a Chinese Han popula- drug) [3]. An Australian study conducted in 2009 showed that 55% tion [7] and one in a patient with North Asian-Indian origins [8], of people consumed regularly (at least once per month) OTC anal- bringing the number of CYP2C9 variants to 56. gesics, including NSAIDs [4]. Two frequent allelic variants have been characterized: The effectiveness of NSAIDs is usually not questioned and CYP2C9*2 (430C>T, rs1799853) and CYP2C9*3 (1075A>C, relies on cyclooxygenase (COX) inhibition but NSAIDs use is as- rs1057910), both resulting in a decreased activity of CYP2C9 [9]. sociated with serious adverse drug reactions, mainly in the gastroin- The frequency of these alleles shows great interethnic differences. testinal tract and the renal and cardiovascular system. Gastrointesti- CYP2C9*2 is absent in Asians and found in 3% of Afro-Americans nal side effects alone are estimated to account for 103,000 hospi- and Ethiopians. In Caucasians, frequency shows an important het- talizations and 16,500 deaths per year in the United States [1]. erogeneity between populations and also between studies in the Pharmacogenetics is the study of the molecular basis of genetic same population, ranging from 8% in Americans to 19% in British factors that may influence the pharmacokinetics (PK) and pharma- [10]. For CYP2C9*3, the distribution is similar with a great hetero- codynamics (PD) of a drug, changing its efficacy and toxicity pro- geneity between Caucasians (from 3% to 16%) and few carriers in file. In the case of NSAIDs, as with other classes of drugs, it is Asians (1-3%) and in Afro-Americans and Ethiopians (1%) [10]. important to understand these individual genetic variations in order In vitro studies show that most NSAIDs are metabolised by to allow treating each patient with the medication that works best CYP2C9: aceclofenac, aspirin, azapropazone, celecoxib, di- for them, with an optimal efficacy and minimal side effects. Ge- clofenac, etodolac, flurbiprofen, ibuprofen, indomethacin, lornoxi- netic polymorphisms are described for all the PK and PD steps of a cam, lumiracoxib, mefenamic acid, meloxicam, naproxen, phenyl- drug: absorption by membrane transporters, metabolism by differ- butazone, piroxicam, rofecoxib, suprofen, tenoxicam and ent enzymes, activity changes affecting PD receptors, elimination valdecoxib [11-14]. The relative contribution of CYP2C9 to the by membrane transporters. To date, relevant polymorphisms for metabolism of NSAIDs differs largely between the different drugs but CYP2C9 plays a major role in the metabolism of most NSAIDs: *Address correspondence to this author at the Division of Clinical Pharma- celecoxib, flurbiprofen, ibuprofen, lornoxicam, lumiracoxib, me- cology and Toxicology, University Hospitals of Geneva, Gabrielle-Perret- fenamic acid, piroxicam and tenoxicam. Even though data is con- Gentil Street 4, 1211 Geneva 14, Switzerland; Tel: +41 22 3729934; Fax: tradictory, CYP2C9 seems to be also a major metabolizing pathway +41 22 3729945; E-mail: [email protected] for diclofenac [11-13, 15]. The metabolism of aspirin is somewhat
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Table 1. Contribution of cytochromes P450 (CYP) to the metabolism of major NSAIDs [12-14].
Major CYP (>40%) Minor CYP (<40%)
Aspirin - CYP2C9
Celecoxib CYP2C9 CYP3A4
Diclofenac CYP2C9 CYP2B6, CYP2D6, CYP2C8, CYP2C19, CYP3A4
Flurbiprofen CYP2C9 -
Ibuprofen CYP2C9 CYP2C8, CYP2C19
Indomethacin CYP2C9 -
Ketoprofen - CYP2C9
Lornoxicam CYP2C9 CYP1A2, CYP2C19
Lumaricoxib CYP2C9 CYP1A2, CYP2C19
Mefenamic acid CYP2C9 -
Meloxicam CYP2C9 CYP3A4
Naproxen CYP2C9 CYP1A2, CYP2C8
Piroxicam CYP2C9 -
Rofecoxib CYP3A4 CYP1A2, CYP2C9
Sulindac - CYP29
Tenoxicam CYP2C9 CYP2C8
different. It is rapidly deacetylated to salicylic acid which is hy- CYP2C9*1/*2 [21]. Another study however showed no difference droxylated by CYP2C9 into gentisic acid, and the further glucu- in celecoxib PK parameters according to the genotype following ronized by UGTs into two glucuronides that are conjugated with multiple dose administration (200 mg twice daily for 15 days) [22]. glycine and salicyluric acid [16] (Table 1). Nevertheless, the Product Information of Celebrex® includes a For aspirin and several of these NSAIDs, PK and PD modifica- warning about poor metabolisers of CYP2C9 with the recommen- tions linked to CYP2C9 polymorphisms have been studied (Table dation to start at half the usual dose, information further mentioned 2). on the FDA website [23]. For diclofenac, 4'-hydroxylation and 3'-hydroxylation is cata- Pharmacokinetic and Pharmacodynamic Modifications in vitro lyzed by CYP2C9. In vitro, the PK of diclofenac is greatly altered and in vivo for CYP2C9*3 with a Km value of 12.6 M versus 3.9 M for the Metabolism of celecoxib is widely catalyzed by CYP2C9 (70- wild-type CYP2C9. No difference was observed for the Vmax re- 90%) in its hydroxycelecoxib metabolite [17]. In vitro, celecoxib sulting in a Vmax/Km value 3.4 times lower for the CYP2C9*3 hydroxylation (Vmax) was reduced in the presence of recombinant variant compared to the wild-type CYP2C9 [24]. These findings CYP2C9*2 and CYP2C9*3 compared to CYP2C9*1 with the ap- were replicated in another study that also evaluated the impact of parent Km unchanged leading to a celecoxib clearance of 66% that CYP2C9*13 (269T>C, rs72558187), a variant found in the Chinese of the wild-type CYP2C9 for CYP2C9*2 and of 9.3% for population, showing an increased Km (24.1 M versus 5.5 M in CYP2C9*3 [18]. The same study showed that in human hepatic CYP2C9*1), a reduced Vmax (9.9 pmol/min/pmol versus 37.2 microsomes, the rate of metabolism of celecoxib was also altered pmol/min/pmol in CYP2C9*1) and a reduced clearance (0.4 with a 59% decrease in heterozygous CYP2C9*1/*3 livers and a l/min/pmol versus 6.9 l/min/pmol in CYP2C9*1) [25]. An in vivo 47% decrease in heterozygous CYP2C9*1/*2 livers compared with study with a single dose of diclofenac (n = 102) showed a urinary the wild-type CYP2C9 [18]. In vivo in humans, two studies showed ratio of diclofenac/4'-OH diclofenac three times higher in carriers that carriers of CYP2C9*3 had a reduced oral clearance compared of CYP2C9*3/*3 compared to homozygous wild-type patients [26]. with homozygous carriers of the wild-type allele, a decreased me- A recent study aiming to evaluate diclofenac metabolism in three tabolite concentration and an increased systemic exposure [18, 19]. Hispanic populations of different ethnicity showed that the mean This effect is marked in the homozygous CYP2C9*3/*3 with an diclofenac/4'-OH diclofenac ratio was statistically higher in increase in AUC of seven times compared with CYP2C9*1/*3 and CYP2C9*1/*3 (0.77±0.19; n=22) compared with CYP2C9*1/*1 CYP2C9*1/*1 individuals [20]. In a child genotyped subjects (0.65±0.24; n=90). This study also pointed out the impact CYP2C9*3/*3, the PK of celecoxib was significantly altered with a of a less studied variant allele, CYP2C9*8 (449G>A, rs) systemic exposure ten times greater and a half-life calculated to be that showed also a higher mean diclofenac/4'-OH diclofenac ratio of 30 hours, compared with a mean of four hours in the three other (0.93±0.33; n=4) [27]. Another study showed however no differ- patients studied where two were CYP2C9*1/*1 and one was ence in diclofenac PK parameters according to the genotype 328 Current Drug Metabolism, 2014, Vol. 15, No. 3 Rollason et al.
Table 2. CYP2C9 and CYP2C8: PK and PD pharmacogenetic modulations of major allelic variants.
Gene Variant Drug PK impact PD impact
In vitro and ex vivo
CYP2C9 *2 (rs1799853) Celecoxib Reduced clearance [18] -
Diclofenac No impact [29] -
Flurbiprofen Increased Km, decreased Vmax and - clearance [31]
*3 (rs1057910) Celecoxib Reduced clearance [18] -
Diclofenac Increased Km and decrease clearance - [24, 25] No impact [29]
Flurbiprofen Increased Km, decreased Vmax and - clearance [31]
Ibuprofen - Increased maximal inhibition of formation of thromboxane B2 and prostaglandin E2 and AUC [34]
Lornoxicam Increased Km, decreased Vmax and - clearance [40, 41]
Mefenamic acid Increased Km, decreased Vmax and - clearance [24]
Piroxicam Increased Km, decreased Vmax and - clearance [24]
Tenoxicam Increased Km, decreased Vmax and - clearance [24]
In vivo
CYP2C9 *2 (rs1799853) NSAIDs in - Increased number of carriers in gastrointestinal general bleeding with NSAIDs [42, 43] No impact on gastrointestinal symptoms [44-47]
Aspirin - No impact on gastrointestinal symptoms [48] No enhanced protective effect on colorectal cancer [49-51]
Celecoxib No impact following multiple dose [22] No reduction of occurrence of adenoma [52]
Diclofenac No impact following multiple dose [22] No impact on occurrence of hepatotoxicity [53, No impact [28, 29] 54]
Flurbiprofen Increased AUC and half-life [32] -
Ibuprofen No effect on clearance [34] Enhanced protective effect on colorectal cancer Reduced clearance of the racemate and [49] S-ibuprofen when correlated with the CYP2C8*3 [36]
Piroxicam Increased AUC [55] Increased thromboxane A2 AUC [55]
Tenoxicam Increased AUC after single or multiple - doses [56, 57]
Pharmacogenetics of NSAIDs Current Drug Metabolism, 2014, Vol. 15, No. 3 329
Table (2) contd…..
Gene Variant Drug PK impact PD impact
*3 (rs1057910) NSAIDs in - Increased number of carriers in gastrointestinal general bleeding with NSAIDs [42, 43, 58] No impact on gastrointestinal symptoms [44-47]
Aspirin - No impact on gastrointestinal symptoms [48] No enhanced protective effect on colorectal cancer [49-51]
Celecoxib Reduced clearance and metabolite concen- Reduced occurrence of adenoma [52] tration and increased AUC [18, 19] No impact following multiple dose [22]
Diclofenac Increased diclofenac/4'-hydroxydiclofenac No impact on occurrence of hepatotoxicity [53, ratio [26, 27] 54] No impact following multiple dose [22] No impact [28-30]
Flurbiprofen Increased AUC and half-life, reduced clear- - ance [32]
Ibuprofen Reduced clearance of the racemate and S- Enhanced protective effect on colorectal cancer ibuprofen [34, 35] [49]
Lornoxicam Increased AUC and half-life of lornoxicam - and decreased AUC of 5'- hydroxylornoxicam in *3 carriers [59]
Lumiracoxib No impact but no *3/*3 in the study [12] -
Naproxen No impact but no *3/*3 in the study [39] -
Piroxicam Increased AUC [55] Increased thromboxane A2 AUC [55]
Tenoxicam Increased AUC after single or multiple - doses [56, 57]
CYP2C8 *2 NSAIDs in - Higher frequency in gastrointestinal bleeding (rs11572103) general patients when combined with *3 [60]
Ibuprofen Increased clearance of both enantiomers [61] -
*3 (rs11572080 NSAIDs in - Higher frequency in gastrointestinal bleeding and general patients [60] rs10509681) No impact on the protective effect in colorectal cancer [62] No association with the occurrence of peptic ulcer disease [47]
Diclofenac Increased diclofenac/5-hydroxydiclofenac - urinary ratio [63]
Ibuprofen Decreased clearance of both enantiomers - [36, 61, 64] Increased clearance of R-ibuprofen [35]
Tenoxicam No association [56] -
330 Current Drug Metabolism, 2014, Vol. 15, No. 3 Rollason et al.
Table (2) contd…..
Gene Variant Drug PK impact PD impact
*4 (rs1058930) NSAIDs in - No association with the occurrence of peptic ulcer general disease [47]
Diclofenac Increased diclofenac/5-hydroxydiclofenac Trend for higher hepatotoxicity [65] urinary ratio [63]
Ibuprofen Decreased clearance of both enantiomers - [61, 64]
Tenoxicam No association [56] - following multiple dose administration (75 mg twice daily for 15 h/ml) and a 30% reduced clearance of the racemate in CYP2C9*3 days) [22]. Similarly, other studies showed no impact of CYP2C9 compared to CYP2C9*1 (0.036 L/h kg versus 0.051 L/h kg respec- polymorphisms on the PK and PD of diclofenac in vitro or in vivo tively). When analyzed by enantiomer, the impact of CYP2C9*3 was [28-30]. greater on S-ibuprofen with an 87% increased AUC (182 μg h/ml In vitro, flurbiprofen is almost exclusively metabolized by versus 97 μg h/ml) and a 45% reduced clearance in CYP2C9*3 com- CYP2C9. In human liver microsomes genotyped CYP2C9*2, the pared to CYP2C9*1 (0.053 L/h kg versus 0.095 L/h kg respectively) Km was increased (8.3 M versus 5.3 M in CYP2C9*1), the [35]. The same correlation was also demonstrated for the CYP2C9*2 Vmax was decreased (3.1 nmol/min/nmol P450 versus 5.9 allele but only when correlated with the CYP2C8*3 allele [36]. This nmol/min/nmol P450 in CYP2C9*1) leading to a decreased clear- was further demonstrated in a PK study that analysed the influence of ance (0.4 versus 1.1 in CYP2C9*1). In CYP2C9*3, these PK values CYP2C9 and CYP2C8 polymorphisms concomitantly and found the were further modified with a Km of 31 M, a Vmax of 2.6 greatest impaired metabolism in a patient that was CYP2C9*1/*2 and nmol/min/nmol P450 and a clearance of 0.1 [31]. CYP2C8*1/*3. The observed AUC in this patient was of 111.0 mg h/L compared to 61.25 mg h/L (53.71-72.89) in the eight In vivo, CYP2C9 polymorphisms were associated with a change CYP2C9*1/*1 volunteers [37]. in the kinetic parameters of flurbiprofen. The mean AUC was 1.7 fold greater in the CYP2C9*1/*3 carriers (51.1±9.3 μg h/ml, Regarding lumiracoxib, the data available from slow metabolis- P<0.05) and 1.4 fold greater in the CYP2C9*1/*2 carriers (40.3±8.7 ers of CYP2C9 showed no alteration in PK compared with the wild- μg h/ml) compared to the wild-type carriers (29.4±6.7 μg h/ml) type carriers but this study, that characterized 97 patients and leading to a statistically reduced clearance in CY2C9*3 carriers healthy volunteers, did not include a single homozygous only. The half-life of flurbiprofen was also longer with a half-life of CYP2C9*3/*3 carrier (12). 6.1±0.6 hours in CYP2C9*1/*3 subjects (P<0.05), 5.8±0.7 hours in Mefenamic acid is metabolized by CYP2C9 in 3’- CYP2C9*1/*2 subjects (P<0.05) and 4.9±0.3 hours in wild-type hydroxymethylmefenamic acid. In vitro, the metabolism of me- subjects [32]. The FDA states that flurbiprofen should be given fenamic acid to 3’-hydroxymethylmefenamic acid is significantly with caution in poor metabolisers of CYP2C9, however without a decreased for the CYP2C9*3 variant compared with the wild-type recommended dose adjustment [23]. CYP2C9. The Km value was of 40.8 M for CYP2C9*3 versus 8.4 Ibuprofen is administered as a racemic mixture of R- and S- M for the wild-type CYP2C9 and the Vmax was of 4.2 ibuprofen. CYP2C9 is the main enzyme involved in the hydroxyla- pmol/min/pmol P450 for CYP2C9*3 versus 14.9 pmol/min/pmol tion of S-ibuprofen [33]. A population PK study showed that the P450 for the wild-type CYP2C9 resulting in a Vmax/Km value for clearance of the racemate and S-ibuprofen was reduced in homozy- the CYP2C9*3 variant of more than eighteen-fold lower than that of gous carriers of the CYP2C9*3 allele with values of 1.52 L/h (95% the wild-type CYP2C9 [24]. CI, 1.33 to 1.74) for CYP2C9*3/*3 carriers compared with heterozy- Although it has been shown that naproxen is metabolized by gous (2.38 L/h, 95% CI, 2.09 to 2.73), or homozygous carriers of the CYP2C9 [38], a study in Koreans has not demonstrated a PK dif- wild-type allele (3.25 L/h, 95% CI 2.84 to 3.73) for S-ibuprofen [34]. ference between homozygous wild-type individuals and carriers of No effect of CYP2C9*2 was observed. This study also evaluated the CYP2C9*1/*3. There was no homozygous CYP2C9*3/*3 carriers PD parameters of ibuprofen by assessing the ex vivo formation of in this study [39]. thromboxane B2, that reflects the COX-1 inhibition and the formation The influence of CYP2C9 polymorphisms on the PK of four of prostaglandin E2 that reflects the COX-2 inhibition. The observed oxicams (lornoxicam, meloxicam, piroxicam and tenoxicam) was PK modifications were reflected in the prostanoids formation. The studied in vitro and in healthy volunteers. For lornoxicam, an in maximal inhibition of thromboxane B2 formation and of prostaglan- vitro study was performed on COS-7 cells (CV-1 in Origin, carry- din E2 and their respective AUCs were larger in carriers of ing SV40), a fibroblast-like cell line derived from the African green CYP2C9*1/*3, CYP2C9*2/*3 and CYP2C9*3/*3 compared with monkey kidney cells that can be transfected to produce recombinant CYP2C9*1/*1 carriers. For example, the AUC of thromboxane B2 proteins for experimentation. This study showed that mean values was of 836 relative inhibition units min for CYP2C9*3/*3 versus 524 of Km were increased for CYP2C9*3 with a value of 1.61 μM for CYP2C9*1/*1 and the the AUC of prostaglandin E2 was of 1058 compared to 1.24 μM in CYP2C9*1 and that mean values of Vmax relative inhibition units min for CYP2C9*3/*3 versus 408 for were decreased (0.28 pmol/min/pmol for CYP2C9*3 carriers versus CYP2C9*1/*1 [34]. A study that evaluated the impact of polymor- 0.83 pmol/min/pmol) with therefore a clearance decreased to 28% phisms on the racemic and enantiomeric form of ibuprofen in healthy in CYP2C9*3 [40]. In addition, this study also showed the impact volunteers found a 30% increased AUC (241 μg h/ml versus 181 μg of CYP2C9*13 on the PK of lornoxicam with a Km value of 2.79 Pharmacogenetics of NSAIDs Current Drug Metabolism, 2014, Vol. 15, No. 3 331
μM, a Vmax of 0.22 pmol/min/pmol and an intrinsic clearance Modification of the Toxicity and Efficacy Profile decreased to 12% compared with the wild-type variant [40], data The evaluation of the clinical impact of these PK changes is further confirmed in vivo [66]. A study where the liver microsomes focused mainly on the occurrence of adverse effects with NSAIDs of a CYP2C9*3/*3 carrier was included showed an 8- to 50-fold rather than a change in the efficacy profile. A retrospective study (n lower clearance for lornoxicam 5'-hydroxylation than did the = 218) evaluated the relationship between polymorphic alleles of CYP2C9*1/*1 samples [41]. An open pharmacokinetic study in CYP2C9 and the risk of gastrointestinal bleeding. This study twelve healthy volunteers, where six were CYP2C9*1/*1 subjects showed that the frequency of polymorphic alleles, either CYP2C9*2 and six were CYP2C9*1/*3 showed that the AUC of lornoxicam or CYP2C9*3, increased in individuals with gastrointestinal bleed- was increased by 60±9.78% (P <0.05) and the AUC of 5'- ing related to NSAIDs and was higher in patients taking drugs me- hydroxylornoxicam decreased by 65±11.75% (P<0.001) in the tabolized by CYP2C9. The odds ratio (OR) for bleeding was 2.5 for heterozygous CYP2C9*1/*3 carriers compared with the heterozygous carriers of mutated alleles and 3.7 for homozygous CYP2C9*1/*1 carriers. The half-life of lornoxicam was also pro- carriers of mutant alleles compared to subjects who did not have a longed by 39±8.35%. No change in Cmax of lornoxicam and 5'- gastrointestinal bleeding [42]. hydroxylornoxicam was observed [59]. Another study showed a higher frequency of carriers of A study on the pharmacokinetics of meloxicam was conducted CYP2C9*1/*3 and CYP2C9*1/*2 in individuals who presented in Koreans and evaluated the impact of CYP2C9*13. CYP2C9*13 gastrointestinal bleeding due to NSAIDs compared to a control is an infrequent allele (0.2-1.0 %) detected in Asian populations group. No difference in the frequency of carriers of the (Chinese, Japanese and Koreans) but not in other populations. CYP2C9*2/*3 between the two groups was observed. Taking into CYP2C9*13 induces a decreased enzyme activity. AUC and Cmax consideration the alleles only, the presence of CYP2C9*3 was asso- of meloxicam were higher, with an increase of 2.43-fold and 1.46- ciated with a higher risk of bleeding (OR: 7.3) [43]. fold respectively, in the CYP2C9*1/*13 group compared to the A more recent study with a larger sample (n = 188) also con- CYP2C9*1/*1 group [67]. The rate of production of thromboxane cluded that there was an increased risk of gastrointestinal bleeding B2, reflecting the PD activity of meloxicam, was also significantly when treated with NSAIDs in association with the presence of the lower. CYP2C9*3 allele [58]. However, several studies did not confirm In vitro, the metabolism of piroxicam to 5’-hydroxypiroxicam these findings. Two small studies (n = 23 and n = 26) did not find a is significantly decreased in the CYP2C9*3 variant compared with link between gastric ulcers caused by NSAIDs and CYP2C9 geno- the wild-type CYP2C9. The Km value was of 61 M for CYP2C9*3 type [44, 45]. No homozygous CYP2C9*3/*3 were included in versus 40 M for the wild-type CYP2C9 and the Vmax was of these studies. Another study in 109 patients showed no apparent 0.019 pmol/min/pmol P450 for CYP2C9*3 versus 0.408 link between CYP2C9 polymorphisms and the occurrence of gas- pmol/min/pmol P450 for the wild-type CYP2C9 resulting in a tropathy or dyspeptic symptoms with NSAIDs [46]. A large study Vmax/Km value for the CYP2C9*3 variant of more than thirty-fold on 1239 Caucasians evaluated whether different single nucleotide lower that of the wild-type CYP2C9 [24]. In vivo, the AUC of pi- polymorphisms (SNP) of the CYP2C gene were associated with roxicam was of 256±97 μg h/ml (P=0.002) in CYP2C9*1/*2 carri- peptic ulcer disease, with or without NSAIDs. Results of this study ers and of 259±95 μg h/ml (P=0.002) in CYP2C9*1/*3 carriers with showed no association between CYP2C9 variant alleles and the no difference between CYP2C9*1/*2 and CYP2C9*1/*3 as com- occurrence of peptic ulcer disease either in users or non-users of pared to 154±37 μg h/ml in CYP2C9*1/*1. This study also evalu- NSAIDs [47]. ated PD parameters of piroxicam with a thromboxane A2 AUC Two studies evaluated the influence of CYP2C9 polymorphisms (also a marker of COX-1 activity) two-fold higher in patients with a on the occurrence of hepatotoxicity with diclofenac. Neither of CYP2C9*2 or a CYP2C9*3 allele [55]. them showed a positive association between being a carrier of a For tenoxicam, the metabolism to 5’-hydroxytenoxicam in vitro CYP2C9*2 or a CYP2C9*3 allele and hepatotoxicity with di- is similarly decreased in the CYP2C9*3 variant compared with the clofenac [53, 54]. wild-type CYP2C9. The Km value was of 90 M for CYP2C9*3 No link between CYP2C9 polymorphisms and the prevalence of versus 28 M for the wild-type CYP2C9 and the Vmax was of gastric disorders in hospitalized patients suffering from a cardio- 0.034 pmol/min/pmol P450 for CYP2C9*3 versus 0.264 vascular disease taking aspirin could be established [48]. pmol/min/pmol P450 for the wild-type CYP2C9 resulting in a Although the risk of gastrointestinal bleeding is clearly related Vmax/Km value for the CYP2C9*3 variant of more than twenty- to the dose of NSAIDs and the PK data show a greater exposure to fold lower that of the wild-type CYP2C9 [24]. In vivo, results for these drugs in carriers of the CYP2C9*2 or the CYP2C9*3 alleles, tenoxicam are similar to those for lornoxicam and piroxicam with a the data currently available in vivo on the increased risk of gastroin- greater exposure to tenoxicam in CYP2C9*2 and CYP2C9*3 sub- testinal bleeding remain at best contradictory. Furthermore, these jects after either a single dose or multiple doses [56, 57]. PD safety studies do not attempt to link their observations to PK In summary, nearly all the NSAIDs for which pharmacogenetic data. Therefore, recommendations for dose adjustment in patients PK data are available regarding CYP2C9 polymorphisms show a carriers of the CYP2C9*2 or CYP2C9*3 variant alleles are to date decreased elimination, either in vitro or in vivo, and therefore a available for celecoxib and flurbiprofen only. Further prospective possible accumulation in CYP2C9*3/*3 individuals mainly but also studies linking PK and PD observations are needed in order to in heterozygous carriers of CYP2C9 mutated alleles (CYP2C9*2, evaluate the necessity for dose adjustment in CYP2C9 variant allele CYP2C9*3, CYP2C9*8 and CYP2C9*13). Similarly, the few stud- carriers. ies that have examined the influence of the CYP2C9 polymor- Regarding efficacy, studies have focused on evaluating if the phisms on the PD of NSAIDs, by evaluating the inhibition of the efficacy of NSAIDs in protecting the occurrence or recurrence of formation of thromboxane A2, thromboxane B or prostaglandin 2 colorectal cancers was influenced by CYP2C9 genotype. Several E2, showed a greater inhibition of COX-1 and COX-2 in the carri- studies have assessed the relation between colorectal cancer and ers of the variant alleles of CYP2C9. CYP2C9. Causes of colorectal cancer are to date not fully under- 332 Current Drug Metabolism, 2014, Vol. 15, No. 3 Rollason et al. stood but genetic and environmental factors combined seem to ex- carriers of CYP2C8*3 allele or CYP2C8*4 compared with wildtype plain the occurrence of this disease. CYPs through their metabolis- homozygous carriers [63]. ing process are known to activate carcinogens and mutagens. As the As mentioned, ibuprofen is administered as a racemic mixture CYP2C accounts for a large part of the CYPs, studies have been and CYP2C8 is involved in hydroxylation of the two enantiomers, carried to identify if polymorphisms in the CYP2C9 gene alone are but mainly of R-ibuprofen [33]. An in vitro study in recombinant linked to colorectal cancer. Available studies have shown contradic- insect cells showed a decreased clearance of R- and S-ibuprofen in tory results and therefore a recent meta-analysis that analysed 13 CYP2C8*3 and CYP2C8*4. For R-ibuprofen, the clearance was of studies summarised the data. The results of this meta-analysis sug- 72.3% for CYP2C8*3 and of 49.7% for CYP2C8*4 compared with gests that CYP2C9 polymorphism alone may not be associated with CYP2C8*1. For S-ibuprofen, the clearance was of 83.4% for the occurrence of colorectal cancer [68]. Aspirin and other CYP2C8*3 and of 47.4% for CYP2C8*4 compared with NSAIDs, in particular celecoxib, have been associated with a de- CYP2C8*1. For CYP2C8*2, the clearance was increased to 110.5% creased occurrence of colorectal cancer [69, 70]. Several studies for R-ibuprofen and 124.6% for S-ibuprofen [61]. A correlation was have therefore attempted to link NSAIDs use and CYP2C9 poly- observed between the presence of the CYP2C8*3 allele and a re- morphisms to the occurrence or recurrence of colorectal cancer. duced clearance of both enantiomers in healthy volunteers [64]. CYP2C9 alleles (CYP2C9*1, CYP2C9*2 and CYP2C9*3) were Homozygous carriers of the CYP2C8*3 allele showed a 10 times determined in 2295 patients with colorectal cancer and 2903 con- reduction in the clearance of ibuprofen compared with that ob- trols and interaction between these genotypes, aspirin, ibuprofen served in homozygous carriers of the CYP2C8 wild-type allele [36]. and colorectal cancer risk were assessed. This study showed that the A PK study that analysed the influence of CYP2C9 and CYP2C8 variant CYP2C9 alleles enhanced the protective effect of ibuprofen polymorphisms concomitantly found the greatest impaired metabo- with a dose-response relationship in relation with the increasing lism in a patient that was CYP2C9*1/*2 and CYP2C8*1/*3 [37]. A number of variant alleles (P=0.02). No effect of CYP2C9 variant single-dose PK study showed however a 20% increase of clearance alleles on the protective effect of aspirin was observed [49]. Similar of R-ibuprofen in CYP2C8*3 carriers compared with CYP2C8*1 (P results were found in a randomized placebo-controlled study aimed < 0.05) [35]. at evaluating the efficacy of aspirin and folate on the prevention of For tenoxicam, a single-dose PK study in 18 healthy volunteers recurrence of colorectal cancer [50] and in a case-control study [51] showed no association between CYP2C8 polymorphisms where the influence of CYP2C9*2 and CYP2C9*3 alleles was as- (CYP2C8*3 and CYP2C8*4 allelic variants) and PK parameters of sessed. Two other studies were performed, a prospective study of this NSAID [56]. 790 women [71] and a prospective cohort analysis of patients in- To date, the impact of CYP2C8 polymorphisms on the PK of cluded in a placebo-controlled randomized study aimed at evaluat- the few NSAIDs metabolised by this cytochrome are inconsistent. ing the efficacy of aspirin and/or folate on the prevention of recur- The trend for the studied allelic variants however seems to be com- rence of colorectal cancer [72]. Both demonstrated that CYP2C9 parable with that of CYP2C9 with the different polymorphisms variant alleles were linked to an increased risk or recurrence of leading to a decreased clearance of NSAIDs. colorectal cancer and this was independent of the intake of aspirin, even though aspirin reduced the overall risk of colorectal cancer. Modification of the Toxicity and Efficacy Profile Finally, a study evaluated the influence of CYP2C9 genotypes on A study showed a trend (P = 0.09) to develop hepatotoxicity to the efficacy of celecoxib in reducing the risk of colorectal cancer. diclofenac in carriers of the CYP2C8*4 allele with seven heterozy- Celecoxib was associated with a reduction of occurrence of ade- gous carriers amongst the 24 cases who developed hepatotoxicity noma compared to placebo with an additional effect of the high- (29%) compared to five heterozygous carriers amongst the 48 con- dose (2 x 400 mg/d) compared with the low dose (2 x 200 mg/d) trols [65]. Another study showed that among patients receiving an only in the patients with the CYP2C9*3 variant allele [52]. NSAID metabolised by CYP2C8 and CYP2C9 and that suffered a None of the available studies attempted to link this PD data on gastrointestinal bleeding, the frequency of carriers of the efficacy of NSAIDs in this setting with the potential PK changes of CYP2C8*3 allele was 0.50 vs. 0.23 for controls (OR 3.4, P = 0.002) NSAIDs due to these different CYP2C9 polymorphisms. and the frequency of the carriers of the allele CYP2C8*3 and CYP2C9*2 combined was 0.40 vs. 0.15 (OR 3.7, P = 0.003) [60]. CYTOCHROME P450 (CYP) 2C8 The study cited above that included 1239 Caucasians evaluated also Cytochrome P450 2C8 (CYP2C8) is also polymorphic with 13 whether CYP2C8*3 and CYP2C9*4 variant alleles were associated allelic variants described to date [6]. Several of these variants lead with peptic ulcer disease, with or without NSAIDs. The results to a decreased activity of the enzyme with CYP2C8*2 (805A>T, showed no association between CYP2C8 variant alleles and the rs11572103) found mainly in African populations, CYP2C8*3 occurrence of peptic ulcer disease either in users or non-users of (416G>A, rs11572080 and 1196A>G, rs10509681) and CYP2C8*4 NSAIDs [47]. (792C>G, rs1058930) in Caucasians and CYP2C8*5 (475delA) in A single study evaluated the impact of CYP2C8*3 genotype on Asians [73]. A linkage disequilibrium has been demonstrated be- the protective effect of 14 different NSAIDs in colorectal cancer tween CYP2C8 and CYP2C9 in several populations, mainly be- and showed no impact of the different genotypes [62]. tween CYP2C8*2 and CYP2C9*3 [36]. Diclofenac, ibuprofen and None of these four studies evaluated simultaneously the poten- tenoxicam are metabolised by CYP2C8 but this CYP is only a mi- tial PK changes due to the different CYP2C8 variant alleles. nor metabolic pathway for these drugs. A recent in vitro study showed that CYP2C8 participates in the metabolism of R-ibuprofen METABOLISM: PHASE II ENZYMES for only 10% and of S-ibuprofen for approximately 13% [74]. URIDINE DIPHOSPHATE GLUCURONOSYLTRANSFERASES (UGT) Pharmacokinetic Modifications in vitro and in vivo Glucuronidation is a widespread metabolism pathway for en- For diclofenac, a study in Spanish healthy volunteers showed dogenous as well as exogenous compounds. This function is cata- that diclofenac/5-hydroxydiclofenac urinary ratio was higher in lyzed by uridine diphosphate glucuronosyltransferases (UGT) and Pharmacogenetics of NSAIDs Current Drug Metabolism, 2014, Vol. 15, No. 3 333
Table 3. Contribution of UGTs to the metabolism of the major NSAIDs [75, 88].
Main UGTs Secondary UGTs Reference
Aspirin 1A9, 1A6 1A1, 1A3, 1A4, 1A7, 2B7 [86]
Celecoxib * * [89]
Diclofenac 1A3, 1A9, 2B4, 2B7 1A6, 2B15. 2B17 [90, 91]
Flurbiprofen 1A9, 2B7 1A1. 1A3, 2B4 [77, 92]
Ibuprofen 1A3, 2B7 1A7, 1A9, 1A10 [85, 93]
Indomethacin 1A3, 1A9, 2B7. 1A1, 1A8, 1A10 [79, 87]
Ketoprofen 2B4, 2B7 1A3, 1A9 [85, 91]
Mefenamic acid 1A9, 2B7 - [94, 95]
Naproxen 2B7 1A1, 1A3, 1A6, 1A7, 1A9, 1A10 [85, 96]
Niflumic acid 1A1, 1A8 1A3, 1A9, 1A10, 2B7, 2B15 [82, 91, 97]
Phenylbutazone 1A3, 1A9 1A1, 1A10 [81]
Piroxicam - * [98]
Rofecoxib 2B7, 2B15 1A9 [80]
Sulindac 1A1, 1A3, 2B7 - [88]
Tenoxicam - * [98]
* These drugs are metabolised by UGTs but the specific UGT involved is unknown consists of the addition of glucuronic acid to polar molecules, thus In vitro, several NSAIDs also have inhibitory effects on facilitating their elimination. For most drugs, this type of metabo- UGT1A1 (diclofenac, diflunisal, indomethacin, ketoprofen, me- lism occurs after the phase I metabolism through CYPs. UGTs are fenamic acid, naproxen and niflumic acid) [99], on the UGT1A9 classified into families, subfamilies and genes. The twenty-two (diflunisal, mefenamic acid, niflumic acid) [97] and UGT2B7 (me- human UGTs are classified into five subfamilies: UGT1A, UGT2A, fenamic acid) [100]. UGT2B, UGT3A and UGT8 [75]. The UGTs relevant for NSAID The main UGT polymorphisms that have been linked with the metabolism are UGT1A and UGT2B, each of which has several PK and PD data of NSAIDs are UGT1A6 and UGT2B7 (Table 4). allelic variants [76]. For UGT1A6, the UGT1A6*2 (c.541A > G, rs2070959 and Numerous NSAIDs are glucuronised by UGTs: derivatives of c.552A > C, rs1105879) is the most common variant. The fre- propionic acid (benoxaprofen, fenoprofen, flurbiprofen [77], ibu- quency is of 17-29% in a predominantly Caucasian population profen, ketoprofen, naproxen, oxaprozin, tiaprofenic acid), deriva- [101] and of 22% in a Japanese population [102]. tives of acetic acid (diclofenac [78], etodolac, indomethacin [79] and zomepirac), derivatives of salicylic acid (aspirin and diflunisal), For UGT2B7, the most frequent allelic variant is the UGT2B7*2 fenamates (niflumic acid [80]), derivatives of the enolic acid (phen- (802C>T, rs7439366). The frequency of the homozygous wild-type ylbutazone [81]) and selective COX-2 inhibitors (celecoxib, ro- gene (UGT2B7*1) and UGT2B7*2 variant is similar in Caucasians fecoxib [82]). Different UGTs are involved in the metabolism of (about 25% each), half of the population being therefore heterozy- NSAIDs, either predominantly or as a minor metabolic pathway: gous UGT2B7*1/*2. In a Japanese population, the homozygous UGT1A1, 1A3, 1A4, 1A6, 1A7, 1A8, 1A9, 1A10, 2B4, 2B7 and frequency is eight times higher for genotype UGT2B7*1/*1 (45%) 2B15 [75, 83-85]. than for genotype UGT2B7*2/*2 (6%), 33 % of the population being heterozygous UGT2B7*1/*2 [103]. However, it seems that Aspirin itself is not glucuronised but is deacetylated to salicylic these polymorphic differences do not affect the glucuronidation of a acid which is then glucuronised by many UGTs, namely UGT1A1, number of substrates of UGT2B7. Studies aimed on specific sub- 1A3, 1A6, 1A7, 1A9, 1A10, 2B4 and 2B7 [86]. strates would help clarify this point. The relative contribution of the different UGTs to the metabo- lism of NSAIDs is difficult to apprehend. An abundant literature is Pharmacokinetic Modifications in vitro and in vivo available on the subject but the existing studies focus mainly on the A study evaluated the impact of UGT1A6 polymorphism on relation between a specific NSAID and a specific UGT, not allow- aspirin. No difference was observed in the salivary PK parameters ing for a comparison of the relative contribution of each UGT. between different allelic variants. Urinary excretion of aspirin and Moreover, experimentations are performed in different condition its metabolites was lower in the early hours of collection (2-4 and even slight variations in pH have shown to alter the effect of hours) in patients with the wild-type allele compared with carriers UGTs on NSAIDs [87]. Table 3 summarizes the available data. of the mutated allele but not in the subsequent measurements [104]. 334 Current Drug Metabolism, 2014, Vol. 15, No. 3 Rollason et al.
Table 4. UGT: PK and PD pharmacogenetic modulations of major allelic variants.
Gene Variant Drug PK impact PD impact
In vitro and ex vivo
UGT1A6 *2 (rs2070959 Aspirin No difference in salivary parameters [104] - and rs1105879) No change in urinary excretion of metabo- lites [105] Lower plasma concentrations of salicylates [106]
UGT2B7 *2 (rs7439366) Flurbiprofen Reduced glucuronidation [92] -
Ibuprofen Lower production of acyl-glucuronide [93] -
In vivo
UGT1A6 *2 (rs2070959 NSAIDs in - No link between genotype and peptic ulcer and rs1105879) general hemorrhage [106]
Aspirin - No link between genotype and upper gastroin- testinal complaints [48] Greater colon cancer risk reduction [51] Prevention of colorectal cancer in women only [107] No link between genotype and colon cancer risk reduction [49, 108]
Ibuprofen No link between genotype and colon cancer risk reduction [49, 108]
UGT2B7 *2 (rs7439366)) Diclofenac More common in diclofenac hepatotoxicity patients [65]
Similarly, the excretion of urinary metabolites of aspirin is unaf- Few PK studies have evaluated the impact of UGT polymor- fected by the different genotypes of UGT1A6 [105]. However, in phisms on the glucuronidation of NSAIDs. The available data show contrast, a study conducted exclusively in women showed a differ- no impact of UGT1A6 polymorphisms on the glucuronidation of ence between the UGT1A6 genotypes with lower plasma concentra- aspirin, a reduced glucuronidation of flurbiprofen and ibuprofen tions of salicylates in carriers of the UGT1A6*2 variant [109]. with UGT2B7 polymorphisms and an increased glucuronidation of An in vitro study showed a change in flurbiprofen glucuronida- flurbiprofen with the UGT1A9*2. tion via UGT2B7 in the presence of mutated allelic variants. The Modification of the Toxicity and Efficacy Profile UGT2B7*2 showed a greatly reduced activity of glucuronidation of flurbiprofen at less than 10% of that of the wild-type allele mainly Regarding toxicity, a study already cited above assessed the due to a reduction in Vmax. For example for S-flurbiprofen, the link between the CYP2C9 and UGT1A6 genotype and upper gastro- intestinal complaints in hospitalized patients with cardiovascular Vmax was of 120 pmol/min/mg protein in UGT2B7*1 and of 7 disorders. None of the UGT polymorphisms tested were associated pmol/min/mg protein in UGT2B7*2. No stereoselective difference with gastrointestinal symptoms due to aspirin [48]. in formation of the metabolites of flurbiprofen was observed in UGT2B7*2, UGT2B7*5 (1192G>A) or UGT2B7*71S (211G>T) One hundred and fourteen patients with a bleeding peptic ulcer [92]. The same study evaluated also the impact of UGT1A9 on were compared with 158 cardiac patients using similar amounts of flurbiprofen, UGT1A9 showed a steroselectivity of glucuronidation NSAIDs and 140 healthy controls that took almost no NSAIDs. The and was more active toward the S enantiomer. UGT1A9*2 (8G>A) frequency of UGT1A6 polymorphisms did not differ between the showed a higher Km, Vmax and clearance than UGT1A9*1. Impact group with ulcer and the two control groups (P = 0.76) leading the of UGT1A9*3 (98T>C) could not be assessed under the conditions authors to conclude that UGT polymorphisms were not involved in of this study, showing a lack of catalytic activity of this allelic vari- gastrointestinal disorders due to NSAIDs [106]. A study examined ant [92]. UGT2B7 genotypes in patients who experienced hepatotoxicity with diclofenac and in patients taking diclofenac without adverse An in vitro study showed that UGT2B7 is involved in the for- effects. The UGT2B7*2 mutation was more common in patients mation of acyl-glycoside metabolites of R- and S-ibuprofen that are with hepatotoxicity than in the control group [65]. potentially toxic metabolites, and that this production, although catalyzed by other co-factors, was significantly different between No studies have assessed the impact of UGT polymorphisms on UGT2B7*1 and UGT2B7*2 with a higher production of metabolites the clinical efficacy of NSAIDs as analgesics. However, several with the wildtype allele [93]. studies have looked at the impact of UGT polymorphisms on the Pharmacogenetics of NSAIDs Current Drug Metabolism, 2014, Vol. 15, No. 3 335 chemoprevention of colorectal cancer by aspirin. A case-control Modification of the Toxicity and Efficacy Profile study showed that carriers of any variant allele of UGT1A6 had a A study on 106 gastrointestinal bleeding patients and 88 con- stronger risk reduction of colon cancer when using aspirin than trols confirmed that NSAIDs were a risk factor for peptic ulcer bleed- wild-type UGT1A6 patients [51]. A prospective, nested case-control ing but found no link between the haplotype variant of PTGS1, study in 1062 women evaluated the efficacy of aspirin in this con- -842A>G (rs10306114)/c.50C>T and the occurrence of peptic ulcer text. Whereas UGT1A6 genotype was not associated with the over- bleeding. No crossed analysis was conducted to link NSAIDs con- all colorectal cancer risk, the benefit of aspirin on the prevention of sumption, PTGS1 variant alleles and the occurrence of this adverse adenomas was limited to the women carriers of the genetic variant event [114]. A study in 40 patients evaluated among other alleles UGT1A6*2 (OR=0.66, 95% CI=0.45-0.95) [107]. Another study the impact of two PTGS1 variant alleles, -842A>G and c.50C>T on evaluated the same outcome in 2295 patients with colorectal cancer gastrointestinal bleeding after low dose aspirin (100 mg). No asso- and 2903 controls and showed no influence of UGT1A6*2 and ciation was demonstrated with the two tested alleles [115]. UGT1A6*4 (c.552A>C, rs1105879) on the prevention of colorectal In an acute coronary syndrome (ACS) cohort, 115 patients ex- cancer with either aspirin or ibuprofen [49]. These data were repli- posed to NSAIDs (rofecoxib, celecoxib and non-selective NSAIDs) cated in another study that analysed separately the two SNPs of the were compared to a cohort of 345 patients. Two PTGS1 SNPs UGT1A6*2 [108]. In a randomized placebo-controlled aspirin trial (rs10303135 and rs12353214) were statistically significantly asso- aimed at evaluating the prevention of colorectal adenoma recur- ciated with ACS. In patients on COX-2 selective inhibitors only, rence, 546 patients were genotyped for UGT1A6*1, UGT1A6*2 and the association was also statistically significant with an OR of 6.94 UGT1A6*4. Patients with one or more variant alleles had a signifi- (IC 95%: 1.35-35.65, P=0.016) for rs10303135 and 7.11 (IC 95%: cant reduced risk of colorectal cancer recurrence (RR: 0.68, 95% 1.38-36.74, P=0.019) for rs12353214 [116]. CI: 0.52-0.89). Further stratification however showed that patients carriers of UGT1A6 variants were at reduced risk of recurrence of In a case-cohort study, another PTGS1 SNP, -1006G>A, the colorectal cancer whether they were in the acetylsalicylic group or variant allele was more frequent in stroke cases than in the non- the placebo group [50]. stroke cases in Caucasians (18.2% versus 10.6%, P=0.027) [117]. None of these PD studies evaluated the link between the In a study in a Japanese population, no -842A>G or c.50C>T safety/efficacy profile of NSAIDs and a change in exposure due to variant alleles were detected and another variant, -1676T>C was PK modifications. studied. To be a carrier of the non-mutated -1676T allele in the COX-1 gene promoter was a significant risk factor for developing PHARMACOLOGICAL TARGETS gastric ulcers. Moreover, the number of -1676T alleles was also linked to an increased risk for NSAID-induced ulcer [118]. Another PTGS1 GENE study by the same authors found again an association between the The PTGS1 gene encodes for prostaglandin-endoperoxide syn- -1676T allele and epigastric pain syndrome in Japanese patients thetase-1 that catalyzes the first steps of the arachidonic acid me- suffering from functional dyspepsia, but in women only, leading to tabolism into prostaglandin. Prostaglandin-endoperoxide syn- assume that these women had a greater chance of gastric adverse thetase-1 has two active sites: a hydroperoxidase and a cyclooxy- events when treated with NSAIDs [119]. genase site, and is commonly named COX-1. COX-1 is the target No association was found between four SNPs in PTGS1, two in for non selective NSAIDs inhibiting this enzyme. COX-1 is a con- the promoter region (c.8592C>T, c.1676C>T) and two in the cod- stitutive enzyme while COX-2 has to be induced. They differ in the ing region (c.22C>T, c.50C>T), and the occurrence of aspirin- regulation of their expression and tissue distribution. Various intolerant asthma or the severity of this disease [120]. PTGS1 variant alleles have been described but their frequency is only known for few of them [110]. Known SNP frequencies are Regarding efficacy, again studies focused on the PTGS1 poly- specific for a precise ethnicity. Frequencies are known for five non morphisms and the protective effect of NSAIDs on the occurrence synonymous mutations in Caucasians, two in Africans and none in of cancer. A recent meta-analysis evaluated the existing data on this Asians [111]. The impact of PTGS1 variant alleles and PD, toxicity subject and selected three studies on PTGS1 c.50C>T polymor- and efficacy of NSAIDs has been evaluated in a few studies. The phism that included enough data to allow estimating the OR [121- most frequent studied alleles are the c.50C>T (rs3842787), 123]. Results showed that NSAIDs users that were homozygous for -842A>G (rs10306114) and the 1676T>C (rs1330344) (Table 5). the C allele had a significantly decreased cancer risk compared with non-NSAID users (OR: 0.73, 95% CI = 0.59-0.89) [124]. A recent Pharmacodynamic Modifications in vitro and in vivo study on the interaction between PTGS1 polymorphisms, NSAIDs use and colon and rectal cancer, not included in the previous meta- An in vitro COX-1 inhibition study using indometacin demon- analysis, found that the NSAID-associated risk reduction for rectal strated that the variant alleles c.50C>T and G230S (rs3842795) cancer was limited to the wild-type c.50C>T (rs3842787) carriers were associated with significantly lower IC50 values as compared of PTGS1 [125]. with wild-type allele, suggesting increased COX-1 inhibition by indometacin [112]. PTGS2 GENE A study in healthy volunteers evaluated the degree and selectiv- PTGS2 gene encodes for prostaglandin-endoperoxide syn- ity of COX-1 and -2 inhibition after celecoxib and rofecoxib intake thetase-2 also catalysing the first step of arachidonic acid metabo- according to PTGS1 alleles. A significant ex vivo and in vivo COX- lism into prostaglandin. Prostaglandin-endoperoxide synthetase-2, 1 inhibition reduction was demonstrated in carriers of the c.50C>T like prostaglandin-endoperoxide synthetase-1, has two active sites: variant allele for both drugs, inhibition demonstrated by a failure of a hydroperoxidase and a cyclooxygenase, and is commonly named inhibition of thromboxane B2. Post-hoc analysis demonstrated no COX-2. COX-2 is the target of NSAIDs inhibiting this enzyme and celecoxib ex vivo COX-1 inhibition as well as no rofecoxib in vivo thus preventing inflammatory mediators’ formation. Many PTGS2 COX-1 inhibition. These data demonstrate that PGTS1 mutations variant alleles have been described but to date none is considered as may have an impact on the selectivity of COX-2 selective NSAIDs a polymorphism because of their low expression frequency in the [113]. gene. Most studies available assessed the influence of these poly- 336 Current Drug Metabolism, 2014, Vol. 15, No. 3 Rollason et al.
Table 5. PTGS: PD pharmacogenetic modulations of major allelic variants.
Gene Variant Drug PD impact
In vitro and ex vivo
PTGS1 c.50C>T (rs3842787) Celecoxib Reduction of COX1 inhibition in T variants [113]
Indometacin Significantly lower IC50 values in T variants [112]
Rofecoxib Reduction of COX1 inhibition in T variants [113]
PTGS2 -765G>C (rs20417) Celecoxib No influence of genotype on COX-2 inhibition [129]
In vivo
PTGS1 c.50C>T (rs3842787) NSAIDs in general Decreased cancer risk in NSAID users homozygous for C allele [124] Decreased rectal cancer risk in NSAID users homozygous for C allele [125]
Aspirin No impact of genotype on gastrointestinal bleeding [115] No association with the occurrence of aspirin-intolerant asthma [130]
-842A>G (rs10306114) Aspirin No impact of genotype on gastrointestinal bleeding [115]
-1676T>C (rs1330344) NSAIDs in general Increased risk of NSAID related gastric ulcer with increasing number of T alleles [118] Increased risk of epigastric pain syndrome and potential susceptibility to ADR with NSAIDs in Japanese women carriers of the T allele [119] No association with the occurrence of aspirin-intolerant asthma [131]
PTGS2 -765G>C (rs20417) NSAIDs in general No influence on occurrence of acute coronary syndrome [132] Reduction of cancer risk in GG [124]
Aspirin Trend for a higher risk of coronary disease in G non- aspirin users [117] Trend for a lower risk of coronary disease in G aspirin users [117] No influence on aspirin intolerant asthma [130, 133] Better efficacy in primary prevention in C carriers [134]
Ibuprofen Pain evaluation lower in C carriers compared to rofecoxib [135]
Rofecoxib Pain evaluation lower in GG compared to ibuprofen [135]
8473T>C (rs 5275) NSAIDs in general No influence on occurrence of acute coronary syndrome [132] Reduced risk of acute coronary syndrome in C carriers [136] Reduction of cancer risk in TT [124] morphisms on the epidemiological risk of developing certain pa- (-765CC) (n=10) evaluated the impact of these genotypes on cele- thologies such as cancer [126] or cardiovascular diseases. Some coxib COX-2 inhibition in an ex-vivo model assessing prostaglan- studies have thus demonstrated a protective effect of various muta- din E2 monocyte production [129]. These polymorphisms had no tions on myocardial infarction and cerebrovascular events [117]. A influence on celecoxib COX-2 inhibition. few studies have assessed the impact of medications on PTGS2 variants. The most studied SNP is -765G>C (rs20417). The C vari- Modification of the Toxicity and Efficacy Profile ant allele is associated with PTGS2 reduced expression [127]. This The impact of PTGS2 polymorphisms, and particularly the variant is present in 14.5% Caucasians, 43.5% Native Ameri- -765G>C SNP (rs20417), on ibuprofen and rofecoxib analgesic cans/Hispanics and 66.7% Africans/Afro-Americans [128] (Table response was assessed in 135 subjects after impacted wisdom teeth 3). extraction. Wild-type homozygotes (GG) reported a lower pain evaluation on a visual analog scale at 48 hours after rofecoxib Pharmacodynamic Modifications in vitro and in vivo intake (7.2±2.5 mm, P=0.008) as compared with ibuprofen intake An in vitro evaluation of two less studied PTGS2 variant al- (31.3±6.7 mm). The opposite was observed in carriers of the leles, Glu488Gly (rs5272) and Val511Ala (rs5273) demonstrated C mutated allele (CC or GC), where pain evaluation was lower after that nimesulide inhibits COX-2 selectively but the residual COX ibuprofen (7±1.9 mm, P=0.002) than after rofecoxib (37±6.8 mm) activity is 30 to 60% higher in the presence of these mutations [135]. [137]. Regarding cardiovascular toxicity, a study evaluated coronary A study in 20 Caucasian healthy volunteers either wild-type artery disease or ischemic stroke after aspirin according to homozygotes for -765GG (n=10) or mutated homozygotes -765G>C polymorphism. Albeit not statistically significant, a trend Pharmacogenetics of NSAIDs Current Drug Metabolism, 2014, Vol. 15, No. 3 337 for a higher risk of coronary disease in carriers of the G allele was A population-based case-control study evaluated the association demonstrated in non-aspirin users and, conversely, a trend for a between NSAIDs use, bladder cancer risk and 39 genes related to lower risk of coronary disease in the same population but aspirin the metabolism of NSAIDs. A reduced risk of bladder cancer in users [117]. The same study showed that in African Americans, the users of ibuprofen was observed in carriers of the T allele of a sin- -765C variant allele was more common in stroke cases [117]. A gle SNP located in CYP3A5 (16304C>T, rs4646450) [149]. second study confirmed that aspirin efficacy in primary prevention is higher in C allele carriers of -765G>C [134]. Transporters A case-control study compared NSAIDs intake in hospitalised The two main renal transporters are the renal organic anion ACS patients versus healthy volunteers. NSAIDs intake the week transporters (OATs) and the organic cation transporters (OCT). prior to hospitalisation was associated with ACS with an OR of OAT1 (SLC22A6) is involved in renal secretion across the baso- 1.8 (1.2, 2.5). The two SNPs -765G>C and 8473T>C (rs5275) did lateral membrane of many anionic NSAIDs such as diclofenac, not influence ACS occurrence after NSAIDs. However, haplotype indomethacin, mefenamic acid, naproxen, phenylbutazone, piroxi- analysis demonstrated a trend for reduced ACS when taking the cam and salicylic acid [150]. Some NSAIDs are inhibitors of OATs selective COX-2 inhibitors celecoxib and rofecoxib in mutated (diclofenac, ibuprofen, indomethacin, phenylbutazone and salicylic patients (-765C/8473C) compared with patients with one or two acid), of organic anion transporting polypeptides OATP (di- copies of -765G and/or 8473T [132]. Another study demonstrated clofenac, ibuprofen, indomethacin, phenylbutazone) and "multiple also a statistically significant association between the 8473C variant drug resistance proteins" MDR (ABCB) and MRP (ABCC) (di- and reduced risk of ACS [136]. clofenac, indomethacin) [151, 152]. SNPs have been identified for several members of these families of transporters [153, 154]. Their No association between three promoter SNPs in PTGS2, impact on the PK of NSAIDs has not been evaluated, although the -765G>C, -1195G>A (rs689466), and 1290A>G (rs689465) and the interactions between NSAIDs and some drugs via these carriers occurrence of aspirin-intolerant asthma was found [130, 138]. have been described [152, 155]. However, mutation in these trans- Regarding efficacy, studies focused also on the PTGS2 poly- porters has been linked to the occurrence of drug-induced liver morphisms and the protective effect of NSAIDs on the occurrence injury for three of them. For ABCB11, the 1331T>C polymorphism of different cancers (colorectal cancer, breast cancer, ovarian can- was associated with an increased risk of developing liver toxicity cer, lung cancer, basal cell carcinoma, prostate cancer). A recent with NSAIDs (OR = 2.9, 95% CI 1.6-5.4, P=0.002) in homozygous meta-analysis evaluated the existing data on this subject and in- carriers of the C allele [156]. The same was recently observed in a cluded 13 studies that evaluated four different PTGS2 polymor- study that included 188 Spanish drug-induced liver injury patients, phisms: PTGS2 8473T>C (eight studies), PTGS2 -765G>C (seven of which 20 patients that had NSAIDs liver injury, with an OR of studies), -1195G>A (three studies) and PTGS2 rs2745557 (three 3.4 (95% CI 1.3-8.6, P=0.007) [157]. In a study that evaluated the studies) [121-123, 139-148]. For PTGS2 8473T>C and for genetic susceptibility of diclofenac hepatotoxicity, the ABCC2 -765G>C, NSAID use significantly reduced cancer risk in individu- -24C>T variant allele was more common in patients that suffered als homozygous for the wild-type allele only compared to non- from liver injury than in hospital (OR 8.5, P=0.03) and healthy NSAID users (OR=0.77, 95% CI=0.66-0.89 for rs5275 and controls (OR 7.7, P=0.005) [65]. OR=0.82, 95% CI=0.70-0.95 for -765G>C). For the two other po- lymorphisms, no association was found between the risk of devel- Other Polymorphisms oping cancer, NSAID use and polymorphisms [124]. A recent study Numerous other polymorphisms are being studied in order to on the interaction between PTGS2 polymorphisms, NSAIDs use assess their impact upon treatment with NSAIDs. For example, a and colon or rectal cancer, not included in the previous meta- genome-wide association study GWAS has shown that some allelic analysis, found that the homozygous carriers of the C allele of variants of human leukocyte antigens (HLA) were associated with -62C>G (rs20424) had a greater protective benefit of NSAIDs for hepatic adverse reactions induced by lumiracoxib [158]. These colon cancer risk [125]. same HLA and variants of the gene ALOX5 that codes for arachido- nate 5-lipoxygenase have been linked to the occurrence of urti- OTHER CANDIDATE GENES caria/angioedema induced by aspirin [159]. Many other gene polymorphisms are currently being studied to A study on the influence of genetic polymorphisms on adenoma explain the interindividual variability in the efficacy and toxicity recurrence and toxicity of celecoxib showed that genetic variants of profile of NSAIDs. However, for many of them, although the avail- numerous genes related to the inflammation process were linked to able data show polymorphisms and it is known that NSAIDs inter- adenoma recurrence, gastrointestinal toxicity and cardiovascular act with the proteins encoded by these genes, the link between the toxicity in the celecoxib group, for example the prostaglandin E2 two has not yet been demonstrated and the real clinical impact has synthetase (PGES), the C-reactive protein (CRP) or genes in- not been assessed. volved in epidermal growth factor receptor signaling (SRC) Other Cytochrome P450 [160]. Several NSAIDs are also metabolised by CYPs other than Inflammatory cytokines, interleukin-1 (IL-1) and tumor ne- CYP2C9 and CYP2C8 and a few studies have been conducted in crosis factor alpha (TNF-) are also polymorphic and several SNPs order to evaluate the impact of these CYPs on NSAID toxicity. have been associated with the occurrence of gastric or duodenal ulcer during NSAID and aspirin treatment (IL-1 -511/-31. IL- The study performed on 1239 Caucasians evaluated also the 1RN, TNF--857/-863/-1031) [115, 161-163]. association between the CYP2C19*17 polymorphism and the occur- Finally, many other polymorphisms have been studied for aspi- rence of peptic ulcer disease, with or without NSAIDs. rin but mainly in terms of its antiplatelet activity [164]. CYP2C19*17 is a variant allele of CYP2C19 that confers the status of ultrarapid metaboliser. Results of this study showed an associa- CONCLUSION tion between CYP2C9*17 and the occurrence of peptic ulcer dis- ease in users and non-users of NSAIDs [47]. The clinical implementation of pharmacogenetic data involves many steps. These steps begin with the identification of polymor- 338 Current Drug Metabolism, 2014, Vol. 15, No. 3 Rollason et al. phisms of genes involved in transport, metabolism, elimination or PD = Pharmacodynamics receptor sites of action of molecules. Then the relationship between PK = Pharmacokinetics gene variants and the in vitro and in vivo impact that these changes SNP = Single nucleotide polymorphism have on the PK and PD of a given drug must be assessed. The final step is to determine whether the link between a genetic polymor- TNF- = Tumor necrosis factor-alpha phism and a drug has real clinical impact and, if this is the case, is UGT = Uridine diphosphate glucuronosyltransferase adaptation of treatment needed. 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Received: November 9, 2013 Revised: January 20, 2014 Accepted: February 3, 2014