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Pharmacogenomics J ; 8(4): 268-77, 2008 Aug.
Article in English | MEDLINE | ID: mdl-17923851

ABSTRACT

Cytochrome P450 2C8 (CYP2C8) plays a major role in the metabolism of therapeutically important drugs which exhibit large interindividual differences in their pharmacokinetics. In order to evaluate any genetic influence on this variation, a CYP2C8 phenotype-genotype evaluation was carried out in Caucasians. Two novel CYP2C8 haplotypes, named B and C with frequencies of 24 and 22% in Caucasians, respectively, were identified and caused a significantly increased and reduced paclitaxel 6alpha-hydroxylation, respectively, as evident from analyses of 49 human liver samples. In healthy white subjects, CYP2C8*3 and the two novel haplotypes significantly influenced repaglinide pharmacokinetics in SLCO1B1c.521T/C heterozygous individuals: haplotype B was associated with reduced and haplotype C with increased repaglinide AUC (0-infinity). Functional studies suggested -271C>A (CYP2C8*1B) as a causative SNP in haplotype B. In conclusion, two novel common CYP2C8 haplotypes were identified and significantly associated with altered rate of CYP2C8-dependent drug metabolism in vitro and in vivo.


Subject(s)
Aryl Hydrocarbon Hydroxylases/genetics , Carbamates/metabolism , Haplotypes/genetics , Paclitaxel/metabolism , Piperidines/metabolism , Aryl Hydrocarbon Hydroxylases/metabolism , Aryl Hydrocarbon Hydroxylases/physiology , Carbamates/pharmacology , Cytochrome P-450 CYP2C8 , Genetic Variation/drug effects , Genetic Variation/genetics , Haplotypes/drug effects , Humans , Paclitaxel/pharmacology , Piperidines/pharmacology , White People/genetics
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