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 anti-inflammatory 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 CYP2C83: 0.50 vs. 0.23 [odds ratio (OR); 95% confidence interval (CI)=3.4; 1.5-7.5; P=0.002], CYP2C92: 0.48 vs. 0.26 (OR; 95% CI=2.7; 1.2-5.8; P=0.013) and CYP2C93: 0.24 vs. 0.20 (OR; 95% CI=1.3; 0.5-3.1; P=0.578). The frequencies for carriers of the CYP2C83+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 CYP2C83 and CYP2C92 (CYP2C83+CYP2C92 genotype), is a relevant determinant in the risk to develop gastrointestinal bleeding in patients receiving NSAID that are CYP2C8/9 substrates.