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Impact of CYP2C9 genotype on pharmacokinetics: are all cyclooxygenase inhibitors the same?

A David Rodrigues1

  • 1Drug Metabolosm, Bristol-Myers Squibb, Princeton, NJ 08543, USA. david.rodrigues@bms.com

Drug Metabolism and Disposition: the Biological Fate of Chemicals
|August 25, 2005
PubMed

Insights

CYP2C9 genotype has minimal impact on the clearance of many cyclooxygenase (COX) inhibitors, but significantly affects others. Patient safety requires considering multiple drug metabolism pathways beyond just CYP2C9.

Area of Science:

  • Pharmacogenomics
  • Drug Metabolism
  • Cardiovascular and Gastrointestinal Safety

Background:

  • Market withdrawals of rofecoxib (Vioxx) and valdecoxib (Bextra) heightened concerns regarding cyclooxygenase (COX) inhibitor side effects.
  • Identifying risk factors for adverse events is crucial for ensuring patient safety with COX inhibitors.

Purpose of the Study:

  • To investigate the potential role of CYP2C9 genotype as a risk factor for adverse effects of COX inhibitors.
  • To determine the clinical significance of CYP2C9 genotype in the pharmacokinetics of various COX inhibitors.

Main Methods:

  • Surveyed multiple COX inhibitors to assess the role of CYP2C9 in their overall drug clearance.
  • Evaluated the impact of CYP2C9 genotype on drug exposure and potential side effect risks.

Main Results:

  • CYP2C9 plays a minor role (<20%) in the clearance of sulindac, naproxen, ketoprofen, diclofenac, rofecoxib, and etoricoxib, rendering genotype impact clinically insignificant.
  • CYP2C9 genotype is expected to influence the clearance of ibuprofen, indomethacin, flurbiprofen, celecoxib, valdecoxib, lornoxicam, tenoxicam, meloxicam, and piroxicam.

Conclusions:

  • CYP2C9 genotype does not significantly impact the pharmacokinetics of several commonly used COX inhibitors.
  • For drugs where CYP2C9 is a major clearance pathway, other factors like CYP2C8 and CYP3A4 activity must also be considered for a comprehensive risk assessment.

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