Ibuprofen (IBU) is a traditional non-steroidal anti-inflammatory drug (NSAID) widely used in the treatment of mild to moderate pain and inflammation. This may be as a short term over-the-counter treatment for headaches, muscle aches or fever reduction or long-term, often prescription use, for arthritis and other chronic conditions. IBU inhibits the cyclooxygenase enzymes COX1 and COX2 coded for by PTGS1 and PTGS2, preventing the formation of various prostaglandins (see the Celecoxib Pathway http://www.pharmgkb.org/pathway/PA152241951 for further details of the pharmacodynamics) [Article:9515184].
The drug is given as a racemic mixture of R and S enantiomers [Article:9515184]. Orally dosed IBU is rapidly and completely absorbed with plasma drug levels showing a linear relationship to dose for commonly used doses (200-400mg) [Article:2109643; 9515184]. Ibuprofen is extensively (>98%) bound to plasma albumin at therapeutic concentrations [Article:9515184].
The primary metabolism of IBU is oxidative and involves the cytochrome P450 enzymes [Article:22226725] (see figure). The major primary metabolites found in urine are carboxy IBU and hydroxy metabolites 2-OH IBU, , 3-OH IBU; with 1-OH IBU a minor product [Article:22226725]. The hydroxy and carboxy metabolites of IBU have no apparent pharmacological activity [Article:9515184]. IBU is almost completely metabolized with little to no unchanged drug found in the urine [Article:22226725]. There are differences in metabolic routes taken by the different enantiomers; metabolism of S-IBU is predominantly via CYP2C9 whereas R-IBU is more via CYP2C8 [Article:9296349](see below for discussion of PGx effects related to the different enantiomers). A number of other CYPs are capable of metabolism at high concentrations of IBU: CYP3A4, CYP2C8, CYP2C19, CYP2D6, CYP2E1, and CYP2B6 for 2-hydroxylation and CYP2C19 for 3-hydroxylation [Article:18787056].
An estimated 50-65% of R-IBU undergoes inversion to the S enantiomer 9515184. Inversion of R-IBU to S-IBU occurs via an acylCoA thioester by the enzyme Alpha-methylacyl-coenzyme A racemase, AMACR [Article:21614403]. This can occur pre-systemically in the gut [Article:9515184] as well as in the liver [Articles:14506641, 23376124].
Secondary metabolism of IBU by glucuronidation occurs via the UGTs [Article:15047194]. In vitro experiments showed that recombinant UGT2B7 had the highest activity with racemic IBU, but UGT1A3 and UGT1A9 also showed activity [Article:15047194]. Covalent binding of IBU-glucuronide to plasma proteins may increase risk for toxicity [Article:7781263]. IBU-glucuronide can account for 4% of plasma drug in the elderly due to decreased clearance [Article:7781263] and may also be elevated in individuals with renal impairment, increasing risk of ADRs [Article:7714818]. Conjugation to thiols has also been reported, although these account for a very small amount (less than 1% of urinary metabolites for all thiols combined)[Article:23052971]. These metabolites are also considered reactive and may contribute to ADRs although studies to date have been in vitro or in model organisms [Article:20946099]
Various classes of transporters interact with NSAIDs: organic anion transporters in the kidney and GI tract (hOAT family), as well as hepatic organic anion transporters (hOATP family), multi-drug resistance protein family of transporters (MRPs) and the intestinal peptide transporter (SLC15A1). IBU is a weak acid and lipid soluble so it is feasible that it may be able to cross membranes without the need for specific transporters [Article:9515184]. It is still unclear which, if any, transporters facilitate uptake of IBU and if this has impact for distribution or clearance, but the interaction of IBU with various transporters has clinical importance for drug-drug interactions (DDIs)[Article:21389119].
The organic anion transporters SLC22A6 (hOAT1), SLC22A7 (hOAT2), SLC22A8 (hOAT3) and SLC22A9 (hOAT4) are capable of uptake of IBU in vitro [Article:12388633]. IBU also interacts with SLC22A6 (hOAT1) and SLC22A8 (hOAT3) to inhibit methotrexate uptake in a Xenopus oocyte expression system [Article:22072415]. For SLC22A6, S-IBU is a stronger inhibitor than R-IBU, but for SLC22A8 both entantiomers inhibit equally [Article:22072415]. This may represent the mechanism by which fatal drug-drug interactions between IBU and methotrexate occur, with clearance of methotrexate becoming inhibited leading to toxic plasma drug levels [Article:22072415]. Another possible mechanism for the DDIs with methotrexate is via the MRP transporters [Article:17005917]. IBU inhibits ABCC2 (MRP2) and ABCC4 (MRP4) uptake of methotrexate in vitro [Article:17005917].
While IBU is not a substrate for the OATPs, SLCO1B1 (hOATP1B1) and SLCO1B3 (hOATP1B3) it does interact with these transporters [Article:21389119]. IBU stimulates increased uptake of pravastatin and inhibits uptake of bromosulfophthalein in vitro [Article:21389119].
IBU is also a non-competitive inhibitor of SLC15A1 (hPEPT1, not depicted) in intestinal epithelial cells in vitro [Article:20726987]. The SLC15A1 transporter facilitates uptake of various anti-biotic and anti-viral drugs and gamma-aminolevulinic acid a drug used in photodynamic cancer therapy [Article:20726987]. It is unclear whether IBU leads to clinically relevant DDIs with these drugs in vivo.
Since NSAIDs are one of the most frequently used classes of drugs; an estimated 6-24% of adults in the US may have used NSAIDs in a given month, therefore safety is paramount [Article:20101062]. The adverse events for IBU given most clinical consideration are gastrointestinal (GI) bleeding, or ulcer, and cardiovascular (CV) events. Data on individual NSAIDs can be difficult to find. While rare serious skin diseases, such as Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported in cases with ibuprofen use, these are exceedingly rare, at a rate of less than 1 per 1 million users per week for most NSAIDs [Article:20101062].
One of the rationales for the design of the selective COX2 inhibitors or coxib family of drugs was the gastrointestinal risk of traditional NSAIDs [Article:23163547]. However, several large studies and meta-analyses suggest that the risk for GI side effects with short-term daily IBU use were mild and not significantly different from acetaminophen or placebo [Article:23163547]. Pharmacogenomic studies suggest that these risks may be modulated by genetic variation [Articles:17681167, 18216720, 20445534].
In the wake of withdrawal of rofecoxib, attention has been paid to the relative CV risk of all NSAIDs. A recent systematic review that looked at thirty-nine studies involving IBU, found an odds ratio of 1.18 (1.11-1.25), or "low-risk" for CV events at low doses [Article:21980265]. However, at higher doses IBU did increase the risk for CV events. In pairwise comparisons IBU was significantly lower risk than diclofenac and etoricoxib, and slightly but still significantly higher risk than naproxen [Article:21980265].
In studies of expressed proteins, CYP2C9 favored S-2-OH IBU and S-3-OH IBU formation whereas CYP2C8 favored R-2-OH IBU formation [Article:9296349]. The relative amounts of the different IBU metabolites may therefore be changed by variation in CYP2C9 and CYP2C8 due to this stereospecific preference. In a study of 30 healthy white Polish volunteers, clearance of IBU was reduced in individuals with loss of function alleles of CYP2C9 and CYP2C8 [Article:19480553]. Those with either CYP2C9*3 (n=7), or CYP2C8*3 (n=5) had lower clearance of racemic mixed IBU than with CYP2C9*1 and CYP2C8*1 (n=16) and those who had both CYP2C8*3 and CYP2C9*2 (n=2) had significantly lower clearance (There were no individuals who had CYP2C9*2 without the CYP2C8*3 allele.) [Article:19480553]. When looking at R-IBU alone, CYP2C8*3 had significantly lower plasma drug levels. The individuals with both CYP2C8*3 and CYP2C9*2 also had significantly lower plasma carboxy IBU, whereas amounts of 2-OH IBU were similar amongst all groups [Article:19480553].
A few studies suggest that this decrease in clearance leading to sustained IBU levels may increase risk for GI events. In a small study of Italian NSAID users (n= 26, 3 of which were IBU users) with gastroduodenal bleeding, there were significantly higher frequencies of CYP2C9*1/*2 and CYP2C9*1/*3 genotypes in cases versus controls [Article:17681167]. The association for CYP2C9*2 and risk for bleeding was also confirmed in a case-control study of Spanish NSAID users (n= 134, 14 of which were IBU users) [Article:18216720]. In the Spanish study CYP2C8*3 was also associated with risk for NSAID-related bleeding, with the combined CYP2C8*3-_CYP2C9*2_ haplotype having further increased risk [Article:18216720]. A study in France representing non-aspirin NSAID users of various ethnicities (n= 57, 11 IBU users), did not replicate the association for CYP2C8 but did see increased risk for CYP2C9*3 and acute upper GI bleeding [Article:20445534].
To date one paper has looked at IBU efficacy and PGx: examining genomic variants and pain perception with either IBU or rofecoxib after surgery for wisdom tooth extraction [Article:16678543]. At 48 hours after surgery, patients with the GG or CG genotype at rs20417 in PTGS2 showed significantly greater reduction in pain with IBU compared to rofecoxib, whereas those with the CC genotype had better response to rofecoxib than IBU [Article:16678543] (NB: this gene is on the minus chromosomal strand, complemented on PharmGKB to the plus strand, in the paper this is reported on the minus strand). The rs20417 variant in PTGS2 is located in the promoter region and effects transcription factor binding. In individuals with the rs20417 CC genotype, PTGS2, and therefore COX2-selective inhibitors, may be of greater consequence for pain than for individuals with the GG or CG genotype where PTGS1 and traditional NSAIDs such as IBU are more effective.
An interesting area of PGx with respect to IBU is how the drug may interact with AMACR variants and modulate cancer risk [Article:23376124]. So far no studies have connected the interaction of IBU with AMACR to genetic variation in AMACR. AMACR is the enzymes responsible for conversion of R to S IBU. AMACR also interacts with pristanic acid, a dietary component that is found in red meat and dairy products and may play a role in its detoxification. AMACR protein levels are increased in prostate cancer cells and a number of other cancers. Variants in AMACR and alternative splice forms have been associated with cancer. As yet, no variants have been shown to interact differently with IBU.
Mazaleuskaya Liudmila L, Theken Katherine N, Gong Li, Thorn Caroline F, FitzGerald Garret A, Altman Russ B, Klein Teri E. "PharmGKB summary: ibuprofen pathways" Pharmacogenetics and genomics (2014).
If you would like to reproduce this PharmGKB pathway diagram:
Entities in the Pathway
Drugs/Drug Classes (3)
Relationships in the Pathway
|Arrow From||Arrow To||Controllers||PMID|
|2-OH ibuprofen||2-OH IBU gluc||22226725|
|3-OH ibuprofen||3-OH IBU gluc||22226725|
|3-OH ibuprofen||carboxyibuprofen||Cytosolic dehydrogenase||9165543, 9296349|
|carboxyibuprofen||carboxy IBU gluc||22226725|
|ibuprofen||2-OH ibuprofen||CYP2C19, CYP2C8, CYP2C9, CYP3A4||22226725|
|ibuprofen||3-OH ibuprofen||CYP2C19, CYP2C9||22226725|
|ibuprofen||ibuprofen-glucuronide||UGT1A3, UGT1A9, UGT2B17, UGT2B4, UGT2B7||15047194|
|methotrexate||methotrexate||ibuprofen, ABCC2, ABCC4||17005917|
|methotrexate||methotrexate||ibuprofen, SLC22A6, SLC22A8, SLC22A9||12130730, 18789319|
|pravastatin||pravastatin||ibuprofen, SLCO1B1, SLCO1B3||21389119|
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