Abstract
The market withdrawals of rofecoxib (Vioxx) and valdecoxib (Bextra) have focused considerable attention on the side effect profiles of cyclooxygenase (COX) inhibitors. As a result, attempts will be made to identify risk factors in the hope that physicians might be able to ensure patient safety. At first glance, CYP2C9 genotype might be considered a risk factor because many COX inhibitors are CYP2C9 substrates in vitro. This observation has led some to hypothesize that a reduction in clearance, in subjects expressing variant forms of the enzyme (e.g., CYP2C9*1/*3 or CYP2C9*3/*3 genotype), will lead to increased exposure and a greater risk of cardiovascular or gastrointestinal side effects. For any drug, however, one has to consider all clearance pathways. Therefore, a number of COX inhibitors were surveyed and it was determined that CYP2C9 plays a relatively minor role in the overall clearance (≤20% of the dose) of sulindac, naproxen, ketoprofen, diclofenac, rofecoxib, and etoricoxib. CYP2C9 genotype would have no clinically meaningful impact on the pharmacokinetics of these drugs. In contrast, CYP2C9 genotype is expected to impact the clearance of ibuprofen, indomethacin, flurbiprofen, celecoxib, valdecoxib, lornoxicam, tenoxicam, meloxicam, and piroxicam. However, even when CYP2C9 is a major determinant of clearance, it is necessary to consider CYP2C8 genotype (e.g., ibuprofen) and, possibly, CYP3A4 activity (e.g., celecoxib, valdecoxib, and meloxicam) also.
Footnotes
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Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
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doi:10.1124/dmd.105.006452.
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ABBREVIATIONS: COX, cyclooxygenase; P450, cytochrome P450; IC50(COX), concentration of inhibitor required to decrease COX activity by 50%; AUCpo(PM), area under the plasma concentration vs. time curve (oral dose) in subjects phenotyped as PM (expressing one or two variant alleles); AUCpo, area under the plasma concentration vs. time curve (oral dose); AUCpo(EM), area under the plasma concentration vs. time curve (oral dose) in subjects phenotyped as EM (expressing two wild-type alleles); [S], substrate concentration; PK, pharmacokinetics; PD, pharmacodynamics; PK-PD, pharmacokinetics-pharmacodynamics; Km, Michaelis constant; Vmax, maximal initial rate of metabolism; NSAID, nonsteroidal anti-inflammatory drug; fh, fraction of dose eliminated in the liver; fm, fraction of total hepatic elimination via all cytochromes P450; fm,CYP, fraction of total cytochrome P450 metabolism catalyzed by an individual cytochrome P450 form; fm,CYP2C9(EM), fraction of total cytochrome P450 metabolism catalyzed by CYP2C9 in EM (wild type, CYP2C9*1/*1) subjects; GI, gastrointestinal; CV, cardiovascular; FMO, flavin-containing monooxygenase; AO, aldehyde oxidase;
, intrinsic (metabolite formation) clearance; , intrinsic (metabolite formation) clearance catalyzed by CYP2C9 (wild type) in EM subjects; , intrinsic (metabolite formation) clearance catalyzed by CYP2C9 (variant forms) in PM subjects; EM, extensive metabolizer phenotype; PM, poor metabolizer phenotype; , total intrinsic clearance (parent consumption); ADME, absorption-distribution-metabolism-excretion; [E], enzyme concentration; kcat, first-order rate constant that relates Vmax to [E]; Cb, concentration of COX inhibitor in blood. - Received July 5, 2005.
- Accepted August 22, 2005.
- The American Society for Pharmacology and Experimental Therapeutics
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