Metabolism of repaglinide by CYP2C8 and CYP3A4 in vitro

effect of fibrates and rifampicin

    Research output: Contribution to journalArticleScientificpeer-review

    Abstract

    "Repaglinide is an antidiabetic drug metabolised by cytochrome P450 (CYP) 2C8 and CYP3A4 enzymes. To clarify the mechanisms of observed repaglinide drug interactions, we determined the contribution of the two enzymes to repaglinide metabolism at different substrate concentrations, and examined the effect of fibrates and rifampicin on CYP2C8, CYP3A4 and repaglinide metabolism in vitro. We studied repaglinide metabolism using pooled human liver microsomes, recombinant CYP2C8 and recombinant CYP3A4 enzymes. The effect of quercetin and itraconazole on repaglinide metabolism, and of gemfibrozil, bezafibrate, fenofibrate and rifampicin on CYP2C8 (paclitaxel 6 alpha-hydroxylation) and CYP3A4 (midazolam 1-hydroxylation) activities and repaglinide metabolism were studied using human liver microsomes. At therapeutic repaglinide concentrations (< 0.4 mu M), CYP2C8 and CYP3A4 metabolised repaglinide at similar rates. Quercetin (25 mu M) and itraconazole (3 mu M) inhibited the metabolism of 0.2 mu M repaglinide by 58% and 71%, and that of 2 mu M repaglinide by 56% and 59%, respectively. The three fibrates inhibited CYP2C8 (K-i: bezafibrate 9.7 mu M, gemfibrozil 30.4 mu M and fenofibrate 92.6 mu M) and repaglinide metabolism (IC50: bezafibrate 37.7 mu M, gemfibrozil 111 mu M and fenofibrate 164 mu M), but had no effect on CYP3A4. Rifampicin inhibited CYP2C8 (K-i 30.2 mu M), CYP3A4 (K-i 18.5 mu M) and repaglinide metabolism (IC50 13.7 mu M). In conclusion, both CYP2C8 and CYP3A4 are important in the metabolism of therapeutic concentrations of repaglinide in vitro, but their predicted contributions in vivo are highly dependent on the scaling factor used. Gemfibrozil is only a moderate inhibitor of CYP2C8 and does not inhibit CYP3A4; inhibition of CYP-enzymes by parent gemfibrozil alone does not explain its interaction with repaglinide in vivo. Rifampicin competitively inhibits both CYP2C8 and CYP3A4, which can counteract its inducing effect in humans."
    Original languageEnglish
    JournalBasic & Clinical Pharmacology & Toxicology
    Volume97
    Issue number4
    Pages (from-to)249-256
    Number of pages8
    ISSN1742-7835
    Publication statusPublished - 2005
    MoE publication typeA1 Journal article-refereed

    Cite this

    @article{2abdf71e870548ebab15f2147411eddc,
    title = "Metabolism of repaglinide by CYP2C8 and CYP3A4 in vitro: effect of fibrates and rifampicin",
    abstract = "{"}Repaglinide is an antidiabetic drug metabolised by cytochrome P450 (CYP) 2C8 and CYP3A4 enzymes. To clarify the mechanisms of observed repaglinide drug interactions, we determined the contribution of the two enzymes to repaglinide metabolism at different substrate concentrations, and examined the effect of fibrates and rifampicin on CYP2C8, CYP3A4 and repaglinide metabolism in vitro. We studied repaglinide metabolism using pooled human liver microsomes, recombinant CYP2C8 and recombinant CYP3A4 enzymes. The effect of quercetin and itraconazole on repaglinide metabolism, and of gemfibrozil, bezafibrate, fenofibrate and rifampicin on CYP2C8 (paclitaxel 6 alpha-hydroxylation) and CYP3A4 (midazolam 1-hydroxylation) activities and repaglinide metabolism were studied using human liver microsomes. At therapeutic repaglinide concentrations (< 0.4 mu M), CYP2C8 and CYP3A4 metabolised repaglinide at similar rates. Quercetin (25 mu M) and itraconazole (3 mu M) inhibited the metabolism of 0.2 mu M repaglinide by 58{\%} and 71{\%}, and that of 2 mu M repaglinide by 56{\%} and 59{\%}, respectively. The three fibrates inhibited CYP2C8 (K-i: bezafibrate 9.7 mu M, gemfibrozil 30.4 mu M and fenofibrate 92.6 mu M) and repaglinide metabolism (IC50: bezafibrate 37.7 mu M, gemfibrozil 111 mu M and fenofibrate 164 mu M), but had no effect on CYP3A4. Rifampicin inhibited CYP2C8 (K-i 30.2 mu M), CYP3A4 (K-i 18.5 mu M) and repaglinide metabolism (IC50 13.7 mu M). In conclusion, both CYP2C8 and CYP3A4 are important in the metabolism of therapeutic concentrations of repaglinide in vitro, but their predicted contributions in vivo are highly dependent on the scaling factor used. Gemfibrozil is only a moderate inhibitor of CYP2C8 and does not inhibit CYP3A4; inhibition of CYP-enzymes by parent gemfibrozil alone does not explain its interaction with repaglinide in vivo. Rifampicin competitively inhibits both CYP2C8 and CYP3A4, which can counteract its inducing effect in humans.{"}",
    author = "Lauri Kajosaari and Jouko Laitila and Neuvonen, {Pertti J} and Backman, {Janne T}",
    year = "2005",
    language = "English",
    volume = "97",
    pages = "249--256",
    journal = "Basic & Clinical Pharmacology & Toxicology",
    issn = "1742-7835",
    publisher = "Wiley",
    number = "4",

    }

    Metabolism of repaglinide by CYP2C8 and CYP3A4 in vitro : effect of fibrates and rifampicin. / Kajosaari, Lauri; Laitila, Jouko; Neuvonen, Pertti J; Backman, Janne T.

    In: Basic & Clinical Pharmacology & Toxicology, Vol. 97, No. 4, 2005, p. 249-256.

    Research output: Contribution to journalArticleScientificpeer-review

    TY - JOUR

    T1 - Metabolism of repaglinide by CYP2C8 and CYP3A4 in vitro

    T2 - effect of fibrates and rifampicin

    AU - Kajosaari, Lauri

    AU - Laitila, Jouko

    AU - Neuvonen, Pertti J

    AU - Backman, Janne T

    PY - 2005

    Y1 - 2005

    N2 - "Repaglinide is an antidiabetic drug metabolised by cytochrome P450 (CYP) 2C8 and CYP3A4 enzymes. To clarify the mechanisms of observed repaglinide drug interactions, we determined the contribution of the two enzymes to repaglinide metabolism at different substrate concentrations, and examined the effect of fibrates and rifampicin on CYP2C8, CYP3A4 and repaglinide metabolism in vitro. We studied repaglinide metabolism using pooled human liver microsomes, recombinant CYP2C8 and recombinant CYP3A4 enzymes. The effect of quercetin and itraconazole on repaglinide metabolism, and of gemfibrozil, bezafibrate, fenofibrate and rifampicin on CYP2C8 (paclitaxel 6 alpha-hydroxylation) and CYP3A4 (midazolam 1-hydroxylation) activities and repaglinide metabolism were studied using human liver microsomes. At therapeutic repaglinide concentrations (< 0.4 mu M), CYP2C8 and CYP3A4 metabolised repaglinide at similar rates. Quercetin (25 mu M) and itraconazole (3 mu M) inhibited the metabolism of 0.2 mu M repaglinide by 58% and 71%, and that of 2 mu M repaglinide by 56% and 59%, respectively. The three fibrates inhibited CYP2C8 (K-i: bezafibrate 9.7 mu M, gemfibrozil 30.4 mu M and fenofibrate 92.6 mu M) and repaglinide metabolism (IC50: bezafibrate 37.7 mu M, gemfibrozil 111 mu M and fenofibrate 164 mu M), but had no effect on CYP3A4. Rifampicin inhibited CYP2C8 (K-i 30.2 mu M), CYP3A4 (K-i 18.5 mu M) and repaglinide metabolism (IC50 13.7 mu M). In conclusion, both CYP2C8 and CYP3A4 are important in the metabolism of therapeutic concentrations of repaglinide in vitro, but their predicted contributions in vivo are highly dependent on the scaling factor used. Gemfibrozil is only a moderate inhibitor of CYP2C8 and does not inhibit CYP3A4; inhibition of CYP-enzymes by parent gemfibrozil alone does not explain its interaction with repaglinide in vivo. Rifampicin competitively inhibits both CYP2C8 and CYP3A4, which can counteract its inducing effect in humans."

    AB - "Repaglinide is an antidiabetic drug metabolised by cytochrome P450 (CYP) 2C8 and CYP3A4 enzymes. To clarify the mechanisms of observed repaglinide drug interactions, we determined the contribution of the two enzymes to repaglinide metabolism at different substrate concentrations, and examined the effect of fibrates and rifampicin on CYP2C8, CYP3A4 and repaglinide metabolism in vitro. We studied repaglinide metabolism using pooled human liver microsomes, recombinant CYP2C8 and recombinant CYP3A4 enzymes. The effect of quercetin and itraconazole on repaglinide metabolism, and of gemfibrozil, bezafibrate, fenofibrate and rifampicin on CYP2C8 (paclitaxel 6 alpha-hydroxylation) and CYP3A4 (midazolam 1-hydroxylation) activities and repaglinide metabolism were studied using human liver microsomes. At therapeutic repaglinide concentrations (< 0.4 mu M), CYP2C8 and CYP3A4 metabolised repaglinide at similar rates. Quercetin (25 mu M) and itraconazole (3 mu M) inhibited the metabolism of 0.2 mu M repaglinide by 58% and 71%, and that of 2 mu M repaglinide by 56% and 59%, respectively. The three fibrates inhibited CYP2C8 (K-i: bezafibrate 9.7 mu M, gemfibrozil 30.4 mu M and fenofibrate 92.6 mu M) and repaglinide metabolism (IC50: bezafibrate 37.7 mu M, gemfibrozil 111 mu M and fenofibrate 164 mu M), but had no effect on CYP3A4. Rifampicin inhibited CYP2C8 (K-i 30.2 mu M), CYP3A4 (K-i 18.5 mu M) and repaglinide metabolism (IC50 13.7 mu M). In conclusion, both CYP2C8 and CYP3A4 are important in the metabolism of therapeutic concentrations of repaglinide in vitro, but their predicted contributions in vivo are highly dependent on the scaling factor used. Gemfibrozil is only a moderate inhibitor of CYP2C8 and does not inhibit CYP3A4; inhibition of CYP-enzymes by parent gemfibrozil alone does not explain its interaction with repaglinide in vivo. Rifampicin competitively inhibits both CYP2C8 and CYP3A4, which can counteract its inducing effect in humans."

    M3 - Article

    VL - 97

    SP - 249

    EP - 256

    JO - Basic & Clinical Pharmacology & Toxicology

    JF - Basic & Clinical Pharmacology & Toxicology

    SN - 1742-7835

    IS - 4

    ER -