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

    Research output: Contribution to journalArticleScientificpeer-review

    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 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."
    Original languageEnglish
    JournalPharmacogenomics Journal
    Volume8
    Issue number4
    Pages (from-to)268-277
    Number of pages10
    ISSN1470-269X
    DOIs
    Publication statusPublished - 2008
    MoE publication typeA1 Journal article-refereed

    Cite this

    @article{0fc5b3d5cd804dde931c373a61d8bb4d,
    title = "Characterization of novel CYP2C8 haplotypes and their contribution to paclitaxel and repaglinide metabolism",
    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 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.{"}",
    author = "C Rodriguez-Antona and Mikko Niemi and Backman, {Janne T} and Lauri Kajosaari and Neuvonen, {Pertti J} and M Robledo and M Ingelman-Sundberg",
    year = "2008",
    doi = "10.1038/sj.tpj.6500482",
    language = "English",
    volume = "8",
    pages = "268--277",
    journal = "Pharmacogenomics Journal",
    issn = "1470-269X",
    publisher = "Nature Publishing Group",
    number = "4",

    }

    Characterization of novel CYP2C8 haplotypes and their contribution to paclitaxel and repaglinide metabolism. / Rodriguez-Antona, C; Niemi, Mikko; Backman, Janne T; Kajosaari, Lauri; Neuvonen, Pertti J; Robledo, M; Ingelman-Sundberg, M.

    In: Pharmacogenomics Journal, Vol. 8, No. 4, 2008, p. 268-277.

    Research output: Contribution to journalArticleScientificpeer-review

    TY - JOUR

    T1 - Characterization of novel CYP2C8 haplotypes and their contribution to paclitaxel and repaglinide metabolism

    AU - Rodriguez-Antona, C

    AU - Niemi, Mikko

    AU - Backman, Janne T

    AU - Kajosaari, Lauri

    AU - Neuvonen, Pertti J

    AU - Robledo, M

    AU - Ingelman-Sundberg, M

    PY - 2008

    Y1 - 2008

    N2 - "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."

    AB - "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."

    U2 - 10.1038/sj.tpj.6500482

    DO - 10.1038/sj.tpj.6500482

    M3 - Article

    VL - 8

    SP - 268

    EP - 277

    JO - Pharmacogenomics Journal

    JF - Pharmacogenomics Journal

    SN - 1470-269X

    IS - 4

    ER -