Genetic predisposition to acute gastrointestinal bleeding after NSAIDs use.
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<0.015), suggesting that the inherited impairment of CYP2C9 activity increases the risk for severe adverse drug reactions after NSAIDs use.
Martínez
Carmen
C
Department of Pharmacology, Medical School, University of Extremadura, Badajoz, Spain.
Blanco
Gerardo
G
Ladero
José M
JM
García-Martín
Elena
E
Taxonera
Carlos
C
Gamito
Francisco G
FG
Diaz-Rubio
Manuel
M
Agúndez
José A G
JA
D000208:Acute Disease; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects*; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics* / Q000378:metabolism; D016009:Chi-Square Distribution; D065729:Cytochrome P-450 CYP2C9; D005260:Female; D006471:Gastrointestinal Hemorrhage / Q000139:chemically induced* / Q000201:enzymology / Q000235:genetics*; D005787:Gene Frequency / Q000235:genetics; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D011110:Polymorphism, Genetic / Q000187:drug effects / Q000502:physiology
D000894:Anti-Inflammatory Agents, Non-Steroidal; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases