title: The effect of erythromycin and fluvoxamine on the pharmacokinetics of intravenous lidocaine.
abstract: Inhibitors of CYP3A4 (cytochrome P450 3A4) have a minor effect on lidocaine pharmacokinetics. We studied the effect of coadministration of the antidepressant fluvoxamine (CYP1A2 inhibitor) and antimicrobial drug erythromycin (CYP3A4 inhibitor) on lidocaine pharmacokinetics in a double-blind, randomized, three-way crossover study. Nine volunteers ingested daily 100 mg fluvoxamine and placebo, 100 mg fluvoxamine and 1500 mg erythromycin, or their corresponding placebos for 5 days. On day 6, 1.5 mg/kg lidocaine was administered IV over 60 min. Concentrations of lidocaine and its major metabolite monoethylglycinexylidide were measured for 10 h. Fluvoxamine alone decreased the clearance of lidocaine by 41% (P < 0.001) and prolonged its elimination half-life from 2.6 to 3.5 h (P < 0.01). During the combination of fluvoxamine and erythromycin, lidocaine clearance was 53% smaller than during placebo (P < 0.001) and 21% smaller than during fluvoxamine alone (P < 0.05). During the combination phase the half-life of lidocaine (4.3 h) was longer than during the placebo (2.6 h; P < 0.001) or fluvoxamine (3.5 h; P < 0.01). We conclude that inhibition of CYP1A2 by fluvoxamine considerably reduces elimination of lidocaine and may increase the risk of lidocaine toxicity. Concomitant use of both fluvoxamine and a CYP3A4 inhibitor such as erythromycin can further increase plasma lidocaine concentrations by decreasing its clearance.
authors.affiliation: *Department of Anaesthesiology and Intensive Care, University of Turku, Turku, Finland; †Department of Anaesthesia, Deaconess Hospital, Helsinki, Finland; and the ‡Department of Clinical Pharmacology and §Department of Anaesthesiology and Intensive Care Medicine, University of Helsinki, Helsinki, Finland.
authors.forename: Klaus T
authors.initials: KT
authors.lastname: Olkkola
authors.forename: Mika H
authors.initials: MH
authors.lastname: Isohanni
authors.forename: Katri
authors.initials: K
authors.lastname: Hamunen
authors.forename: Pertti J
authors.initials: PJ
authors.lastname: Neuvonen
mesh_terms: D000328:Adult; D018592:Cross-Over Studies; D065609:Cytochrome P-450 CYP1A2 Inhibitors; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D004311:Double-Blind Method; D004347:Drug Interactions; D004917:Erythromycin / Q000494:pharmacology*; D005260:Female; D016666:Fluvoxamine / Q000494:pharmacology*; D006801:Humans; D007262:Infusions, Intravenous; D008012:Lidocaine / Q000493:pharmacokinetics*; D008297:Male
chemical_list: D065609:Cytochrome P-450 CYP1A2 Inhibitors; D065607:Cytochrome P-450 Enzyme Inhibitors; D004917:Erythromycin; D008012:Lidocaine; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D016666:Fluvoxamine