Effect of fluvoxamine and erythromycin on the pharmacokinetics of oral lidocaine

    Tutkimustuotos: ArtikkelijulkaisuArtikkeliTieteellinenvertaisarvioitu

    Kuvaus

    "Lidocaine is metabolized by cytochrome P450 3A4 (CYP3A4) and CYP1A2 enzymes, but inhibitors of CYP3A4 have had only a minor effect on its pharmacokinetics. We studied the effect of co-administration of fluvoxamine (CYP1A2 inhibitor) and erythromycin (CYP3A4 inhibitor) on the pharmacokinetics of lidocaine in a double-blind, randomized, three-way cross-over study. Eight healthy volunteers ingested daily either 100 mg fluvoxamine and placebo, 100 mg fluvoxamine and 1500 mg erythromycin, or their corresponding placebos (control) for five days. On day 6, 1 mg/kg lidocaine was administered orally. Plasma concentrations of lidocaine, monoethylglycinexylidide (MEGX) and 3-hydroxylidocaine (3-OH-lidocaine) were measured for 10 hr. During the fluvoxamine phase the area under the plasma concentration-time curve (AUC) and peak concentration (C-max) of oral lidocaine were 305% (P < 0.001) and 220% (P < 0.05) of the control values. During the combination of fluvoxamine and erythromycin, lidocaine AUC was 360% (P < 0.001) and C-max 250% (P < 0.05) of those during placebo. Fluvoxamine alone had no statistically significant effect on the half-life of lidocaine (t(1/2)), but during the combination phase t(1/2) (3.8 hr) was significantly longer than during the placebo phase (2.4 hr; P < 0.01). Fluvoxamine alone and in the combination with erythromycin decreased MEGX peak concentrations by approximately 50% (P < 0.001) and 30% (P < 0.01), respectively. We conclude that inhibition of CYP1A2 by fluvoxamine considerably reduces the presystemic metabolism of oral lidocaine and may increase the risk of lidocaine toxicity if lidocaine is ingested. The concomitant use of both fluvoxamine and a CYP3A4 inhibitor like erythromycin may further increase plasma lidocaine concentrations."
    Alkuperäiskielienglanti
    LehtiBasic & Clinical Pharmacology & Toxicology
    Vuosikerta99
    Numero2
    Sivut168-172
    Sivumäärä5
    ISSN1742-7835
    TilaJulkaistu - 2006
    OKM-julkaisutyyppiA1 Alkuperäisartikkeli tieteellisessä aikakauslehdessä, vertaisarvioitu

    Lainaa tätä

    @article{ecb4e6d292694a43be2802c89c549cc4,
    title = "Effect of fluvoxamine and erythromycin on the pharmacokinetics of oral lidocaine",
    abstract = "{"}Lidocaine is metabolized by cytochrome P450 3A4 (CYP3A4) and CYP1A2 enzymes, but inhibitors of CYP3A4 have had only a minor effect on its pharmacokinetics. We studied the effect of co-administration of fluvoxamine (CYP1A2 inhibitor) and erythromycin (CYP3A4 inhibitor) on the pharmacokinetics of lidocaine in a double-blind, randomized, three-way cross-over study. Eight healthy volunteers ingested daily either 100 mg fluvoxamine and placebo, 100 mg fluvoxamine and 1500 mg erythromycin, or their corresponding placebos (control) for five days. On day 6, 1 mg/kg lidocaine was administered orally. Plasma concentrations of lidocaine, monoethylglycinexylidide (MEGX) and 3-hydroxylidocaine (3-OH-lidocaine) were measured for 10 hr. During the fluvoxamine phase the area under the plasma concentration-time curve (AUC) and peak concentration (C-max) of oral lidocaine were 305{\%} (P < 0.001) and 220{\%} (P < 0.05) of the control values. During the combination of fluvoxamine and erythromycin, lidocaine AUC was 360{\%} (P < 0.001) and C-max 250{\%} (P < 0.05) of those during placebo. Fluvoxamine alone had no statistically significant effect on the half-life of lidocaine (t(1/2)), but during the combination phase t(1/2) (3.8 hr) was significantly longer than during the placebo phase (2.4 hr; P < 0.01). Fluvoxamine alone and in the combination with erythromycin decreased MEGX peak concentrations by approximately 50{\%} (P < 0.001) and 30{\%} (P < 0.01), respectively. We conclude that inhibition of CYP1A2 by fluvoxamine considerably reduces the presystemic metabolism of oral lidocaine and may increase the risk of lidocaine toxicity if lidocaine is ingested. The concomitant use of both fluvoxamine and a CYP3A4 inhibitor like erythromycin may further increase plasma lidocaine concentrations.{"}",
    author = "Isohanni, {Mika H} and Neuvonen, {Pertti J} and Olkkola, {Klaus T}",
    year = "2006",
    language = "English",
    volume = "99",
    pages = "168--172",
    journal = "Basic & Clinical Pharmacology & Toxicology",
    issn = "1742-7835",
    publisher = "Wiley",
    number = "2",

    }

    Effect of fluvoxamine and erythromycin on the pharmacokinetics of oral lidocaine. / Isohanni, Mika H; Neuvonen, Pertti J; Olkkola, Klaus T.

    julkaisussa: Basic & Clinical Pharmacology & Toxicology, Vuosikerta 99, Nro 2, 2006, s. 168-172.

    Tutkimustuotos: ArtikkelijulkaisuArtikkeliTieteellinenvertaisarvioitu

    TY - JOUR

    T1 - Effect of fluvoxamine and erythromycin on the pharmacokinetics of oral lidocaine

    AU - Isohanni, Mika H

    AU - Neuvonen, Pertti J

    AU - Olkkola, Klaus T

    PY - 2006

    Y1 - 2006

    N2 - "Lidocaine is metabolized by cytochrome P450 3A4 (CYP3A4) and CYP1A2 enzymes, but inhibitors of CYP3A4 have had only a minor effect on its pharmacokinetics. We studied the effect of co-administration of fluvoxamine (CYP1A2 inhibitor) and erythromycin (CYP3A4 inhibitor) on the pharmacokinetics of lidocaine in a double-blind, randomized, three-way cross-over study. Eight healthy volunteers ingested daily either 100 mg fluvoxamine and placebo, 100 mg fluvoxamine and 1500 mg erythromycin, or their corresponding placebos (control) for five days. On day 6, 1 mg/kg lidocaine was administered orally. Plasma concentrations of lidocaine, monoethylglycinexylidide (MEGX) and 3-hydroxylidocaine (3-OH-lidocaine) were measured for 10 hr. During the fluvoxamine phase the area under the plasma concentration-time curve (AUC) and peak concentration (C-max) of oral lidocaine were 305% (P < 0.001) and 220% (P < 0.05) of the control values. During the combination of fluvoxamine and erythromycin, lidocaine AUC was 360% (P < 0.001) and C-max 250% (P < 0.05) of those during placebo. Fluvoxamine alone had no statistically significant effect on the half-life of lidocaine (t(1/2)), but during the combination phase t(1/2) (3.8 hr) was significantly longer than during the placebo phase (2.4 hr; P < 0.01). Fluvoxamine alone and in the combination with erythromycin decreased MEGX peak concentrations by approximately 50% (P < 0.001) and 30% (P < 0.01), respectively. We conclude that inhibition of CYP1A2 by fluvoxamine considerably reduces the presystemic metabolism of oral lidocaine and may increase the risk of lidocaine toxicity if lidocaine is ingested. The concomitant use of both fluvoxamine and a CYP3A4 inhibitor like erythromycin may further increase plasma lidocaine concentrations."

    AB - "Lidocaine is metabolized by cytochrome P450 3A4 (CYP3A4) and CYP1A2 enzymes, but inhibitors of CYP3A4 have had only a minor effect on its pharmacokinetics. We studied the effect of co-administration of fluvoxamine (CYP1A2 inhibitor) and erythromycin (CYP3A4 inhibitor) on the pharmacokinetics of lidocaine in a double-blind, randomized, three-way cross-over study. Eight healthy volunteers ingested daily either 100 mg fluvoxamine and placebo, 100 mg fluvoxamine and 1500 mg erythromycin, or their corresponding placebos (control) for five days. On day 6, 1 mg/kg lidocaine was administered orally. Plasma concentrations of lidocaine, monoethylglycinexylidide (MEGX) and 3-hydroxylidocaine (3-OH-lidocaine) were measured for 10 hr. During the fluvoxamine phase the area under the plasma concentration-time curve (AUC) and peak concentration (C-max) of oral lidocaine were 305% (P < 0.001) and 220% (P < 0.05) of the control values. During the combination of fluvoxamine and erythromycin, lidocaine AUC was 360% (P < 0.001) and C-max 250% (P < 0.05) of those during placebo. Fluvoxamine alone had no statistically significant effect on the half-life of lidocaine (t(1/2)), but during the combination phase t(1/2) (3.8 hr) was significantly longer than during the placebo phase (2.4 hr; P < 0.01). Fluvoxamine alone and in the combination with erythromycin decreased MEGX peak concentrations by approximately 50% (P < 0.001) and 30% (P < 0.01), respectively. We conclude that inhibition of CYP1A2 by fluvoxamine considerably reduces the presystemic metabolism of oral lidocaine and may increase the risk of lidocaine toxicity if lidocaine is ingested. The concomitant use of both fluvoxamine and a CYP3A4 inhibitor like erythromycin may further increase plasma lidocaine concentrations."

    M3 - Article

    VL - 99

    SP - 168

    EP - 172

    JO - Basic & Clinical Pharmacology & Toxicology

    JF - Basic & Clinical Pharmacology & Toxicology

    SN - 1742-7835

    IS - 2

    ER -