Interaction of CYP2C8 and CYP2C9 genotypes modifies the risk for nonsteroidal anti-inflammatory drugs-related acute gastrointestinal bleeding

Objectives To analyze whether gene variants leading to impaired drug metabolism are related with acute gastrointestinal bleeding after nonsteroidal antiinflammatory drugs (NSAID) use. Methods Common CYP2C8 and CYP2C9 polymorphisms were studied in a cross-sectional study, involving 134 NSAID-related bleeding patients and in 177 patients receiving NSAID with no adverse effects. Results Among patients receiving NSAID that are CYP2C8/9 substrates the frequencies for carriers of variant alleles versus control patients were CYP2C8*3: 0.50 vs. 0.23 [odds ratio (OR); 95% confidence interval (CI)= 3.4; 1.5-75; P=0.002], CYP2C9*2: 0.48 vs. 0.26 (OR; 95% CI = 2.7; 1.2-5.8; P= 0.013) and CYP2C9*3: 0.24 vs. 0.20 (OR; 95% CI = 1.3; 0.5-3.1; P= 0.578). The frequencies for carriers of the CYP2C8*3 + CYP2C9*2 genotype were 0.40 vs. 0.15 (OR; 95% CI = 3.7; 1.6-8.9; P= 0.003). These findings were not influenced by sex, age, smoking or drinking habits. Among bleeding patients receiving NSAID that are not extensively metabolized by CYP2C8/9, no differences in genotypes or allele frequencies were observed as compared with control patients. Conclusion The combined presence of CYP2C8*3 and CYP2C9*2 (CYP2C8*3 + CYP2C9*2 genotype), is a relevant determinant in the risk to develop gastrointestinal bleeding in patients receiving NSAID that are CYP2C8/9 substrates. Pharmacogenetics and Genomics 18:37-43 (c) 2008 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.