Cytochrome P450 2C9 Variants Influence Response to Celecoxib for Prevention of Colorectal Adenoma

Gastrointestinal Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA.
Gastroenterology (Impact Factor: 13.93). 03/2009; 136(7):2127-2136.e1. DOI: 10.1053/j.gastro.2009.02.045
Source: PubMed

ABSTRACT 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.
We identified individuals with CYP2C9*2 and CYP2C9*3 genotypes (>or=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.
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.
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.

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    • "This process removes all the liquids (water and organic) at once, thus the nanodroplets of the drug solution convert into nanoparticles of the drug, together with all the non-volatile components of the microemulsion. The celecoxib that is used here as a model for a water-insoluble drug (Fig. 1a), is a specific cyclooxygenase-2 (COX-2) inhibitor that is successfully used for treating arthritis (Detrembleur et al., 2005; Kivitz et al., 2007; Yelland et al., 2007), pain alleviating (Lu et al., 2006), treating familial adenomatous polyposis and preventing colorectal adenocarcinomas (Dannenberg and Subbaramaiah, 2003; Bertagnolli et al., 2006; Auman et al., 2008; Chan et al., 2009). The aqueous solubility of celecoxib is 3–7 ␮g/ml at pH 7 and 40 • C. The absolute bioavailability after oral administration of the solid dosage form of celecoxib in dogs is 22–40% (Paulson et al., 2001). "
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