Characterization of novel CYP2C8 haplotypes and their contribution to paclitaxel and repaglinide metabolism

C Rodriguez-Antona, Mikko Niemi, Janne T Backman, Lauri Kajosaari, Pertti J Neuvonen, M Robledo, M Ingelman-Sundberg

    Forskningsoutput: TidskriftsbidragArtikelVetenskapligPeer review

    Sammanfattning

    "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 6 alpha-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."
    Originalspråkengelska
    TidskriftPharmacogenomics Journal
    Volym8
    Nummer4
    Sidor (från-till)268-277
    Antal sidor10
    ISSN1470-269X
    DOI
    StatusPublicerad - 2008
    MoE-publikationstypA1 Tidskriftsartikel-refererad

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