Genetically based impairment in CYP2C8- and CYP2C9-dependent NSAID metabolism as a risk factor for gastrointestinal bleeding: is a combination of pharmacogenomics and metabolomics required to improve personalized medicine?

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Agundez JA, Garcia-Martin E, Martinez C

Expert Opin Drug Metab Toxicol. 2009 Jun;5(6):607-20. doi: 10.1517/17425250902970998 .

PubMed ID

19422321 [ View in PubMed

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Abstract

Polymorphisms in CYP2C8 and CYP2C9 are common in all the human populations and many CYP2C8 and CYP2C9 gene variations cause decreased enzyme activity towards the NSAIDs aceclofenac, celecoxib, diclofenac, ibuprofen, indomethazine, lornoxicam, meloxicam, naproxen, piroxicam, tenoxicam and valdecoxib. This impairment in drug biodisposition alters drug pharmacokinetics, with carriers of detrimental mutations displaying increased values of AUC and decreased drug clearance. Individuals carrying the gene variants CYP2C8*3 (rs11572080; rs10509681), CYP2C9*2 (rs1799853) or CYP2C9*3 (rs1057910) show increased risk of developing acute gastrointestinal bleeding during the use of NSAID that are CYP2C8 or CYP2C9 substrates. However, it is not known whether parent drugs or products of alternative metabolic pathways are responsible for bleeding. We present an overview of the current knowledge of relevant polymorphisms of CYP2C8 and CYP2C9 genes, their association with NSAID metabolism and pharmacokinetics and a meta-analysis that confirms the clinical significance of these gene variations with regard to gastrointestinal bleeding.

DrugBank Data that Cites this Article

Drug Enzymes

Drug	Enzyme	Kind	Organism	Pharmacological Action	Actions
Meloxicam	Cytochrome P450 2C8	Protein	Humans	Unknown	Substrate	Details
Naproxen	Cytochrome P450 2C8	Protein	Humans	Unknown	Substrate	Details
Valdecoxib	Cytochrome P450 2C9	Protein	Humans	Unknown	Substrate Inhibitor	Details