Cytochrome P450 2C9 (CYP2C9)

CYP2C9 is an enzyme that is responsible for breaking down (metabolizing) several of the drugs that are commonly used today. Some medications, such as celecoxib, warfarin, and phenytoin require CYP2C9 in order for the medication to be metabolized to forms that are not active and are more easily eliminated from the body. There are other medications that may be affected by CYP2C9.

Many differences exist in the CYP2C9 gene. These differences in the CYP2C9 gene lead to the production of an enzyme with normal to no function. A system designed to classify patients into 3 metabolizer categories based on the ability of their CYP2C9 to break down drugs is used by clinicians to help guide drug therapy decisions.

Intermediate metabolizers – These patients metabolize drugs at a rate somewhere between the poor and normal metabolizers. About 25 percent of people are intermediate metabolizers.

• Drugs that may need to be avoided or have their doses decreased:
  • Meloxicam. Blood levels of meloxicam are expected to be high in some intermediate metabolizers of CYP2C9, and side effects (such as hypertension, gastrointestinal bleeding, and myocardial infarction) may be more likely. If meloxicam is preferred in these patients, it is recommended to decrease the normal starting dose by 50%. Other medications such as aspirin, celecoxib, diclofenac, etoricoxib, flurbiprofen, ibuprofen, ketorolac (for short-term use of up to 5 days), lornoxicam, metamizole, naproxen, parecoxib, sulindac, and valdecoxib should be considered. 
  • Phenytoin: Blood levels of phenytoin are expected to be high in some intermediate metabolizers of CYP2C9. Side effects may be more likely. Initial loading doses of phenytoin should remain the same. If phenytoin is preferred for maintenance therapy it is recommended to decrease the initial maintenance dose by 25% and follow-up with therapeutic drug monitoring.
  • Piroxicam. Blood levels of piroxicam are expected to be high in some intermediate metabolizers of CYP2C9, and side effects (such as hypertension, gastrointestinal bleeding, and myocardial infarction) may be more likely. Other medications such as aspirin, celecoxib, diclofenac, etoricoxib, flurbiprofen, ibuprofen, ketorolac (for short-term use of up to 5 days), lornoxicam, metamizole, naproxen, parecoxib, sulindac, and valdecoxib should be considered. 
  • Tenoxicam. Blood levels of tenoxicam are expected to be high in some intermediate metabolizers of CYP2C9, and side effects (such as hypertension, gastrointestinal bleeding, and myocardial infarction) may be more likely. Other medications such as aspirin, celecoxib, diclofenac, etoricoxib, flurbiprofen, ibuprofen, ketorolac (for short-term use of up to 5 days), lornoxicam, metamizole, naproxen, parecoxib, sulindac, and valdecoxib should be considered.
  • Warfarin: The anticoagulation effect of warfarin may be greater in intermediate metabolizers of CYP2C9. It is recommended to use a validated clinical algorithm that includes CYP2C9 genotype to calculate the initial dose of warfarin in these patients and to monitor the INR. Warfarin dosing is also affected by the VKORC1 genotype test result and in some cases by the CYP4F2 genotype test result. 

Poor metabolizers – These patients have little or no working CYP2C9. About 1 percent of people are poor metabolizers.

• Drugs that may need to be avoided or have their doses decreased:
  • Celecoxib. Blood levels of celecoxib are expected to be high in poor metabolizers of CYP2C9, and side effects (such as hypertension, gastrointestinal bleeding, and myocardial infarction) may be more likely. If celecoxib is preferred in these patients, it is recommended to decrease the normal starting dose of celecoxib by at least 50%.  Consider using other medications such as aspirin, diclofenac, etoricoxib, ketorolac (for short-term use of up to 5 days), metamizole, naproxen, parecoxib, sulindac, and valdecoxib.
  • Flurbiprofen. Blood levels of flurbiprofen are expected to be high in poor metabolizers of CYP2C9, and side effects (such as hypertension, gastrointestinal bleeding, and myocardial infarction) may be more likely. If flurbiprofen is preferred in these patients, it is recommended to decrease the normal starting dose by at least 50%.  Other medications such as aspirin, diclofenac, etoricoxib, ketorolac (for short-term use of up to 5 days), metamizole, naproxen, parecoxib, sulindac, and valdecoxib should be considered. 
  • Ibuprofen. Blood levels of ibuprofen are expected to be high in poor metabolizers of CYP2C9, and side effects (such as hypertension, gastrointestinal bleeding, and myocardial infarction) may be more likely. If ibuprofen is preferred in these patients, it is recommended to decrease the normal starting dose by at least 50%.  Other medications such as aspirin, diclofenac, etoricoxib, ketorolac (for short-term use of up to 5 days), metamizole, naproxen, parecoxib, sulindac, and valdecoxib should be considered. 
  • Lornoxicam. Blood levels of lornoxicam are expected to be high in poor metabolizers of CYP2C9, and side effects (such as hypertension, gastrointestinal bleeding, and myocardial infarction) may be more likely. If lornoxicam is preferred in these patients, it is recommended to decrease the normal starting dose by at least 50%.  Other medications such as aspirin, diclofenac, etoricoxib, ketorolac (for short-term use of up to 5 days), metamizole, naproxen, parecoxib, sulindac, and valdecoxib should be considered. 
  • Meloxicam. Blood levels of meloxicam are expected to be high in poor metabolizers of CYP2C9, and side effects (such as hypertension, gastrointestinal bleeding, and myocardial infarction) may be more likely. Other medications such as aspirin, diclofenac, etoricoxib, ketorolac (for short-term use of up to 5 days), metamizole, naproxen, parecoxib, sulindac, and valdecoxib should be considered. 
  • Phenytoin: Blood levels of phenytoin are expected to be high in poor metabolizers of CYP2C9, and side effects may be more likely. Initial loading doses of phenytoin should remain the same. If phenytoin is preferred for maintenance therapy, it is recommended to decrease the initial maintenance dose by 50% and to follow-up with therapeutic drug monitoring.
  • Piroxicam. Blood levels of piroxicam are expected to be high in poor metabolizers of CYP2C9, and side effects (such as hypertension, gastrointestinal bleeding, and myocardial infarction) may be more likely. Other medications such as aspirin, celecoxib, diclofenac, etoricoxib, flurbiprofen, ibuprofen, ketorolac (for short-term use of up to 5 days), lornoxicam, metamizole, naproxen, parecoxib, sulindac, and valdecoxib should be considered.
  • Tenoxicam. Blood levels of tenoxicam are expected to be high in poor metabolizers of CYP2C9, and side effects (such as hypertension, gastrointestinal bleeding, and myocardial infarction) may be more likely. Other medications such as aspirin, celecoxib, diclofenac, etoricoxib, flurbiprofen, ibuprofen, ketorolac (for short-term use of up to 5 days), lornoxicam, metamizole, naproxen, parecoxib, sulindac, and valdecoxib should be considered.
  • Warfarin: The anticoagulation effect of warfarin is expected to be greater in poor metabolizers of CYP2C9. It is recommended to use a validated clinical algorithm that includes CYP2C9 genotype to calculate the initial dose of warfarin in these patients and to monitor the INR. Warfarin dosing is also affected by the VKORC1 genotype test result and in some cases by the CYP4F2 genotype test result.

Routine phenotypes

Most CYP2C9 medicines don’t need to be adjusted based on the following genotypes:

Normal metabolizer – These patients have normal CYP2C9 function. About 74 percent of people are normal metabolizers.

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