Document Detail


Clinical consequences of cytochrome P450 2C9 polymorphisms.
MedLine Citation:
PMID:  15637526     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The gene coding for the cytochrome P450 (CYP) enzyme 2C9 (CYP2C9) carries numerous inherited polymorphisms. Those coding for R144C (*2) and I359L (*3) amino acid substitutions have both significant functional effects and appreciable high population frequencies, and their in vivo consequences have been studied in humans with regard to drug metabolism. This review summarizes present knowledge about the pharmacokinetics, drug responses, and outcomes of clinical studies in individuals with different CYP2C9 genotypes. Tentative estimates of how CYP2C9 genotyping might be applied to dose adjustments in clinical therapy were based on dose-related pharmacokinetic parameters such as clearance or trough drug concentrations. Mean clearances in homozygous carriers of the *3 allele were below 25% of that of the wild type for S -warfarin, tolbutamide, glipizide, celecoxib, and fluvastatin. In the more frequent heterozygous carriers (genotype *1/*3), the clearances were between 40% and 75%. In these cases in which individual dosages are derived from clinical drug effects, such as for the oral anticoagulants, the pharmacogenetics-based dose adjustments showed a good correlation with the genotype-specific empirically derived doses. In addition to its role in pharmacokinetics, CYP2C9 contributes to the metabolism of fatty acids, prostanoids, and steroid hormones, and it may catalyze potentially toxic bioactivation reactions. However, our current understanding of the role of CYP2C9 in biotransformation of endogenous signaling molecules and in drug toxicity is relatively meager.
Authors:
Julia Kirchheiner; Jürgen Brockmöller
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Publication Detail:
Type:  Journal Article; Review    
Journal Detail:
Title:  Clinical pharmacology and therapeutics     Volume:  77     ISSN:  0009-9236     ISO Abbreviation:  Clin. Pharmacol. Ther.     Publication Date:  2005 Jan 
Date Detail:
Created Date:  2005-01-07     Completed Date:  2005-02-02     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0372741     Medline TA:  Clin Pharmacol Ther     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1-16     Citation Subset:  AIM; IM    
Affiliation:
Department of Pharmacology, University of Cologne, 50931 Köln, Germany. julia.kirchheiner@uk-koelen.de
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MeSH Terms
Descriptor/Qualifier:
Alleles
Anti-Inflammatory Agents, Non-Steroidal / adverse effects,  pharmacokinetics
Aryl Hydrocarbon Hydroxylases / genetics*,  physiology
Genetics, Population*
Genotype
Humans
Metabolic Clearance Rate / genetics
Pharmacogenetics*
Pharmacokinetics*
Polymorphism, Genetic / genetics*
Warfarin / pharmacokinetics
Chemical
Reg. No./Substance:
0/Anti-Inflammatory Agents, Non-Steroidal; 81-81-2/Warfarin; EC 1.14.14.1/Aryl Hydrocarbon Hydroxylases; EC 1.14.14.1/CYP2C9 protein, human

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