Non-steroidal anti-inflammatory drugs (NSAIDs)

Some individuals have genetic variants in the CYP2C9 gene (which encodes the cytochrome P450 2C9 enzyme) that can significantly alter the metabolism and clearance of non-steroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen, flurbiprofen, celecoxib, piroxicam, tenoxicam and meloxicam. This can potentially increase the risk of NSAID-related adverse drug reactions, including gastrointestinal bleeding, renal damage and adverse cardiovascular events.

NSAIDs are widely used medicines that relieve pain, reduce inflammation and help alleviate fever. Some short-acting NSAIDs (for example, ibuprofen) can be purchased over the counter.

There is significant variability between patients in susceptibility to NSAID adverse drug reactions, including gastrointestinal bleeding, hypertension, myocardial infarction, heart failure and renal damage. This variability is thought to be, in part, influenced by genetic variation.

• Metabolism by CYP2C9 contributes extensively to the inactivation of specific NSAIDs mentioned above (ibuprofen, flurbiprofen, celecoxib, piroxicam, tenoxicam and meloxicam).
• The CYP2C9 gene is highly variable (polymorphic), with over 61 different alleles.
• The most commonly reported alleles are categorised into the following functional groups:
  • normal function (CYP2C9*1): an assigned activity value of 1.0;
  • decreased function (CYP2C9*2, *5, *8 and *11): an assigned activity value of 0.5; and
  • no function (CYP2C9*3, *6 and *13): an assigned activity value of 0.
• The combination of an individual’s CYP2C9 alleles determines their CYP2C9 diplotype (often referred to as their genotype). The sum of the activity values of the CYP2C9 alleles an individual carries determines their CYP2C9 activity score, which in turn can be used to determine their genetically predicted CYP2C9 metaboliser phenotype (‘CYP2C9 phenotype’). CYP2C9 phenotypes are typically categorised as follows:
  • Normal metaboliser (activity score of 2).
  • Intermediate metaboliser (activity score of 1 or 1.5).
  • Poor metaboliser (activity score of 0 or 0.5).
• Substantial evidence links CYP2C9 phenotype to plasma NSAID concentrations. CYP2C9 phenotype potentially influences the risk of NSAID-related adverse events, with poor metabolisers likely at greatest risk of adverse events due to reduced drug clearance.
• Other factors can also affect NSAID drug clearance, such as hepatic impairment or advanced age; further caution should be exercised in these individuals.

• At the time of writing, CYP2C9 testing is not available via the National Genomic Test Directory.
• Patients may present with information on their CYP2C9 alleles from other healthcare systems, clinical trials or direct-to-consumer genomic testing (caution should be exercised when interpreting results from non-validated genomic tests).
• The Clinical Pharmacogenetics Implementation Consortium (CPIC) has produced prescribing guidelines for those with known CYP2C9 phenotypes.

For further information, see Results: Patient with a known CYP2C9 genotype requiring NSAIDs.

For clinicians

• CPIC: Supplementary material: Guideline for CYP2C9 and nonsteroidal anti-inflammatory drugs (PDF, 46 pages)
• NHS England: National Genomic Test Directory
• PharmGKB: Annotation of CPIC Guideline for celecoxib, flurbiprofen, ibuprofen, lornoxicam and CYP2C9
• PharmGKB: Annotation of CPIC Guideline for meloxicam and CYP2C9
• PharmGKB: Annotation of CPIC Guideline for piroxicam and CYP2C9
• PharmGKB: Annotation of CPIC Guideline for tenoxicam and CYP2C9

References:

• Daly AK, Rettie AE, Fowler DM and others. ‘Pharmacogenomics of CYP2C9: Functional and Clinical Considerations’. Journal of Personalized Medicine 2017: volume 8, issue 1. DOI: 10.3390/jpm8010001
• Theken KN, Lee CR, Gong L and others. ‘Clinical Pharmacogenetics Implementation Consortium Guideline (CPIC) for CYP2C9 and Nonsteroidal Anti-Inflammatory Drugs‘. Clinical Pharmacology & Therapeutics 2020: volume 108, issue 2, pages 191–200. DOI: 10.1002/cpt.1830

For patients

• St Jude’s Children’s Research Hospital: Cytochrome P450 2C9 (CYP2C9) and medicines (please note that this test is not available on the NHS at the time of writing)