Impact of genetic variation on response to therapy
Hepatic CYP2C9 enzymes contribute to the metabolism of ibuprofen. The activity of CYP2C9 enzymes is influenced by genetic variation in the CYP2C9 gene which can have an impact on drug exposure and the risk of adverse drug reactions.
CYP2C9 poor metabolisers are expected to have markedly reduced metabolism and an increase in plasma concentrations of ibuprofen compared to normal metabolisers. This may increase the probability or severity of adverse drug reactions. Ibuprofen adverse drug reactions include gastrointestinal bleeding, cardiotoxicity, hypertension, and nephrotoxicity.
Ibuprofen is a widely used analgesic with a range of recommended doses requiring individual adjustment according to response. Knowledge of a patient’s CYP2C9 metaboliser phenotype may help guide this by identifying patients who are at increased risk of experiencing adverse drug reactions.
Testing recommendations
At the time of publication there are no UK recommendations for CYP2C9 genotype testing to guide the use of ibuprofen.
Therapeutic recommendations
CYP2C9 metaboliser status unknown
- Initiate treatment with standard starting dose and titrate according to response.
- Use the lowest effective dose for the shortest duration necessary to control symptoms.
CYP2C9 Normal metabolisers: Activity score 2.0
Some examples of CYP2C9 genotypes include: *1/*1
- Initiate treatment with standard starting dose and titrate according to response.
- Use the lowest effective dose for the shortest duration necessary to control symptoms.
CYP2C9 Intermediate metabolisers: Activity score 1.5
Some examples of CYP2C9 genotypes include: *1/*2
- Mildly reduced metabolism compared to normal metabolisers.
- Initiate treatment with standard starting dose and titrate according to response.
- Use the lowest effective dose for the shortest duration necessary to control symptoms.
- Further caution should be taken in individuals carrying the CYP2C9*2 allele (see Further information).
CYP2C9 Intermediate metabolisers: Activity score 1.0
Some examples of CYP2C9 genotypes include: *1/*3, *2/*2
- Moderately reduced metabolism compared to normal metabolisers. Higher plasma concentrations may increase risk of adverse drug reactions.
- Initiate treatment with lowest recommended starting dose and titrate according to response.
- Use the lowest effective dose for the shortest duration necessary to control symptoms.
- Further caution should be taken in individuals carrying the CYP2C9*2 allele (see Further information).
CYP2C9 Poor metabolisers: Activity score 0.5 or 0.0
Some examples of CYP2C9 genotypes include: *2/*3, *3/*3
- Greatly reduced metabolism compared to normal metabolisers. Higher plasma concentrations may increase risk and severity of adverse drug reactions.
- Initiate treatment with 25-50% of recommended starting dose and titrate cautiously according to response to no more than 50% of the maximum recommended dose.
- Use the lowest effective dose for the shortest duration necessary to control symptoms and monitor for adverse drug reactions.
- Alternatively, consider a therapy without significant CYP2C9 metabolism, especially if additional risk factors for NSAID toxicity are present (see Further information).
- Further caution should be taken in individuals carrying the CYP2C9*2 allele (see Further information).
Further information
Additional risk factors for NSAID toxicity
The impact of genetic variation should be considered alongside additional individual risk factors for adverse drug reactions with NSAIDs, such as older age, drug interactions, and co-morbidities. Consult the SmPC for details of drug interactions and additional risk factors.
Additional advice for individuals carrying the CYP2C9*2 allele
Due to linkage disequilibrium, in many populations >80% of individuals who carry the CYP2C9*2 allele also carry the loss-of-function CYP2C8*3 allele in the CYP2C8 gene. This may be of clinical relevance since ibuprofen is a substrate of both CYP2C8 and CYP2C9. In CYP2C9 intermediate and poor metabolisers, further caution should be taken with ibuprofen use in individuals carrying the CYP2C9*2 allele as they may be at higher risk of increased drug exposure and adverse drug reactions than their metaboliser phenotype alone predicts. Linkage disequilibrium is the non-random association of alleles at different loci within a population. It occurs when combinations of alleles appear together more frequently than expected by chance, typically because they are physically close on the same chromosome.
Alternative NSAIDs in CYP2C9 poor metabolisers
Alternative NSAIDs not known to be significantly impacted by CYP2C9 variation include naproxen, diclofenac and aspirin.
References
Viatris (2025). Brufen 400mg Tablets SmPC. Available at: https://www.medicines.org.uk/emc/product/6713/smpc Accessed online 14th April 2026.
Clinical Pharmacogenetics Implementation Consortium CPIC® (2020) Guideline for CYP2C9 and Nonsteroidal Anti-Inflammatory Drugs. Available at: https://www.clinpgx.org/guideline/PA166251464 Accessed online 14th April 2026.
