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Aims To study the effect of CYP2C8*3, the most common CYP2C8 variant allele on the dis-position of (R)-ibuprofen and the association of CYP2C8*3 with variant CYP2C9 alleles. Methods Three hundred and fifty-five randomly selected Spanish Caucasians were screened for the common CYP2C8 and CYP2C9 mutations. The pharmacokinetics of (R)-ibuprofen were studied in 25 individuals grouped into different CYP2C8 genotypes. Results The allele frequency of CYP2C8*3 (0.17) was found to be higher than that reported for other Caucasian populations (P = 0.0001). The frequencies of CYP2C9*2 and CYP2C9*3 were 0.19 (0.16–0.21) and 0.10 (0.08–0.12), respectively. An association between CYP2C8*3 and CYP2C9*2 alleles was observed, occurring together at a frequency 2.4-fold higher than expected for a random association of alleles (P = 0.0001). The presence of the CYP2C8*3 allele was found to influence the pharmacokinetics of (R)-ibuprofen in a gene–dose effect manner. Thus, after administration of 400 mg ibuprofen, the plasma half-life (95% confidence intervals) for individuals with genotypes CYP2C8*1/*1, CYP2C8*1/*3 and CYP2C8*3/*3, was 2.0 h (1.8–2.2), 4.2 h (1.9–6.5; P

Impaired drug metabolism is a major cause of adverse drug reactions, and it is often caused by mutations at genes coding for drug-metabolising enzymes. Two amino-acid polymorphisms of cytochrome P4502C9 (CYP2C9), an enzyme involved in the metabolism of several nonsteroidal anti-inflammatory drugs (NSAIDs), were studied in 94 individuals with acute bleeding after NSAIDs use and 124 individuals receiving NSAIDs with no adverse effects. The frequency of CYP2C9 variant alleles was increased in overall bleeding patients, with a significant trend to higher risk with increasing number of variant alleles (P=0.02). The odds ratio for bleeding patients receiving CYP2C9 substrates (n=33) was 2.5 for heterozygous and 3.7 for homozygous carriers of mutations (P

Cytochrome P-450 CYP2C9 enzyme is involved in the metabolism of xenobiotics and carcinogens. Variant alleles CYP2C9*2 and CYP2C9*3 encode enzymes with altered properties, and CYP2C9*2 has been related to lung cancer risk. The frequency of CYP2C9 variant alleles was analyzed in genomic DNA from 104 patients with lung cancer and in 197 healthy controls. No statistically significant differences in CYP2C9 genotypes, allele frequencies or predicted phenotypes were observed between overall patients and controls. Unconditional logistic regression for the interaction smoking/genotype indicate P values of 0.66 and 0.62 for carriers of CYP2C9*2 and CYP2C9*3, respectively, versus individuals without these mutations. The P values for the same interaction in carriers of one and two mutated genes were 0.56 and 0.67, respectively, versus individuals homozygous for non-mutated genes. Independent analyses of histological types of lung cancer also indicated the absence of statistically significant differences as compared to healthy subjects. Association between CYP2C9 polymorphism and lung cancer risk was not identified in this study.

To analyze whether gene variants leading to impaired drug metabolism are related with acute gastrointestinal bleeding after nonsteroidal anti-inflammatory drugs (NSAID) use.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.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; 1.5-7.5; 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.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.

Objective: To search for ethnic variability in the impact of cytochrome P 450 2C9 (CYP2C9) polymorphism. Methods: CYP2C9 allelic variants related to impaired CYP2C9 metabolism were analysed in genomic DNA from 157 Spanish healthy subjects using amplification–restriction and sequencing procedures. Results: The frequency for CYP2C9 mutated alleles is higher among the Spanish subjects analysed than that reported for other Caucasian individuals: CYP2C9*2, 0.143 and CYP2C9*3, 0.162 (P=0.0001). Nearly 10% of the individuals studied are expected to metabolise deficiently CYP2C9 substrates. Conclusion: In some Caucasian populations the impact of the CYP2C9 polymorphism may be much higher than that estimated from genotyping studies published to date.