Cytochrome P450 2C9 variants influence response to celecoxib for prevention of colorectal adenoma Journal Article
| Authors: | Chan, A. T.; Zauber, A. G.; Hsu, M.; Breazna, A.; Hunter, D. J.; Rosenstein, R. B.; Eagle, C. J.; Hawk, E. T.; Bertagnolli, M. M. |
| Article Title: | Cytochrome P450 2C9 variants influence response to celecoxib for prevention of colorectal adenoma |
| Abstract: | Background & Aims: Variants in the cytochrome P450 2C9 (CYP2C9) gene are associated with impaired metabolism of celecoxib. We examined the influence of CYP2C9*2 (R144C) and CYP2C9*3 (I359L) variants on dose-related response or toxicity in a randomized trial of celecoxib. Methods: We identified individuals with CYP2C9*2 and CYP2C9*3 genotypes (≥1 variant allele) in the Adenoma Prevention with Celecoxib trial. Following adenoma removal, patients were assigned randomly to groups given placebo or low-dose (200 mg twice daily) or high-dose (400 mg twice daily) celecoxib and underwent follow-up colonoscopies at 1 and/or 3 years. Results: Among 1660 patients, 21% were CYP2C9*2, and 12% were CYP2C9*3 genotypes. Overall, celecoxib was associated with a dose-dependent reduction in adenoma, compared with placebo, with relative risks (RR) of 0.65 (95% confidence interval [CI]: 0.56-0.76) for the low-dose and 0.54 (95% CI: 0.46-0.63) for the high-dose groups. However, the additional protective effect of the high dose, compared with the low-dose, was observed only in those with CYP2C9*3 genotypes (RR, 0.51; 95% CI: 0.30-0.87). The high dose, compared with low dose, was not associated with significant risk reduction among those with CYP2C9*2 (RR, 0.83; 95% CI: 0.57-1.21) or wild-type (RR, 0.89; 95% CI: 0.72-1.11) genotypes. Compared with placebo, a higher incidence of cardiovascular events was associated with both doses among patients with wild-type genotypes but only with the high dose among patients with variant genotypes. Conclusions: The greater efficacy of high-dose celecoxib, compared with the low-dose, in preventing colorectal adenoma appears confined to individuals with slow metabolizer (CYP2C9*3) genotypes. Genetic variability influences susceptibility to the potential benefits and hazards of celecoxib. © 2009 AGA Institute. |
| Keywords: | adult; controlled study; human tissue; treatment outcome; treatment response; aged; aged, 80 and over; middle aged; major clinical study; clinical trial; cancer risk; dose response; drug dose comparison; drug efficacy; gastrointestinal hemorrhage; hypertension; drug megadose; follow-up studies; sensitivity and specificity; genetic predisposition to disease; cancer prevention; low drug dose; controlled clinical trial; kidney disease; randomized controlled trial; drug administration schedule; genetic variability; genotype; gene frequency; genetic variation; dose-response relationship, drug; wild type; risk assessment; colorectal neoplasms; confidence intervals; adenoma; probability; acetylsalicylic acid; celecoxib; cardiovascular disease; cardiovascular risk; colorectal adenoma; digestive system ulcer; pyrazoles; sulfonamides; reference values; cytochrome p450 2c9; cytochrome p450 2c9 gene; drug metabolism; aryl hydrocarbon hydroxylases; pharmacogenetics |
| Journal Title: | Gastroenterology |
| Volume: | 136 |
| Issue: | 7 |
| ISSN: | 0016-5085 |
| Publisher: | Elsevier Inc. |
| Date Published: | 2009-06-01 |
| Start Page: | 2127 |
| End Page: | 2136.e1 |
| Language: | English |
| DOI: | 10.1053/j.gastro.2009.02.045 |
| PUBMED: | 19233181 |
| PROVIDER: | scopus |
| PMCID: | PMC2693443 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 10" - "Export Date: 30 November 2010" - "CODEN: GASTA" - "Source: Scopus" |
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