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ANESTHETIC PHARMACOLOGY

The Effect of Erythromycin and Fluvoxamine on the Pharmacokinetics of Intravenous Lidocaine

Klaus T. Olkkola, MD, PhD^*, Mika H. Isohanni, MD, Katri Hamunen, MD, PhD, and Pertti J. Neuvonen, MD, PhD

*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

Address correspondence to Klaus T. Olkkola, MD, PhD, Professor and Chairman, Department of Anaesthesiology and Intensive Care, Turku University Hospital, PO Box 52 (Kiinamyllynkatu 4–8), FIN-20521 Turku, Finland. Address e-mail to klaus.olkkola{at}tyks.fi.

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.