Genetic predisposition to acute gastrointestinal bleeding after NSAIDs use

Abstract

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 antiinflammatory 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 ¼ 0.02). The odds ratio for bleeding patients receiving CYP2C9 substrates (n ¼ 33) was 2.5 for heterozygous and 3.7 for homozygous carriers of mutations (Po0.015), suggesting that the inherited impairment of CYP2C9 activity increases the risk for severe adverse drug reactions after NSAIDs use.

Effects of the Antifungals Voriconazole and Fluconazole on the Pharmacokinetics of S -(+)- and R -(−)-Ibuprofen

“…Accordingly, increased exposure to ibuprofen due to inhibition of CYP2C9 by voriconazole or fluconazole might increase the risk of the concentration-dependent renal, cardiovascular, or gastrointestinal adverse drug reactions caused by ibuprofen. This assumption is supported by the findings of a study reporting that the impaired metabolism of ibuprofen due to mutations in the CYP2C9 gene increases the risk of acute gastrointestinal bleeding (21). On the basis of the results of …”

Pharmacogenetics, Drug-Metabolizing Enzymes, and Clinical Practice

“…The presence of CYP2C9*2 or *3 was associated with increased risk of a GI bleeding episode (odds ratio 1.64; 95% CI 1.05, 2.58). This was due largely to *2, which was present in 23.4% of individuals with bleeding episodes compared with 13.7% in control subjects (*3 occurred in 8.5% of both groups) (Martinez et al, 2004a). The association of CYP2C9*2 with increased GI bleeding is at odds with the available pharmacokinetic data suggesting that NSAIDs are affected minimally by this variant.…”

“…10, 6.19). In this analysis, diclofenac was also considered as a drug metabolized extensively by CYP2C9, although previous studies have not supported a relationship between CYP2C9 variants and diclofenac pharmacokinetics (Martinez et al, 2004a). A third study investigated the pharmacokinetics of piroxicam, indomethacin, diclofenac, and naproxen in patients with and without a history of GI bleeding with these drugs.…”

Significance of pharmacogenetic testing in solution of problem of nonsteroid antirheumatic drugs administration gastro-intestinal safety

“…Martınez и соавт. изучили полиморфизм гена CYP2С9 у 94 больных с острым желудочно -кишечным кровотечением на фоне лечения НПВП (основная группа) и у 124 больных без подобных осложнений (контрольная группа Было показано, что наследственное снижение активности CYP2С9 может повышать риск разви-тия желудочно -кишечных кровотечений на фоне лечения НПВП [17].…”