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Prediction by Pharmacogenetics of Safety and Efficacy of Non-Steroidal Anti- Inflammatory Drugs: a Review

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Prediction by Pharmacogenetics of Safety and Efficacy of Non-Steroidal Anti- Inflammatory Drugs: a Review 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 1875-5453/14 $58.00+.00 © 2014 Bentham Science Publishers Pharmacogenetics of NSAIDs Current Drug Metabolism, 2014, Vol. 15, No. 3 327 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].
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