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% (PϽ0.001) and 220% (PϽ0.05) of the control values. During the combination of fluvoxamine and erythromycin, lidocaine AUC was 360% (PϽ0.001) and C max 250% (PϽ0.05) 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; PϽ0.01). Fluvoxamine alone and in the combination with erythromycin decreased MEGX peak concentrations by approximately 50% (PϽ0.001) and 30% (PϽ0.01), 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.Lidocaine is an amide-type local anaesthetic widely used for infiltration anaesthesia. It can be applied also to mucous membranes of the oral cavity and ingested after spraying it into the upper respiratory and gastrointestinal tract. Lidocaine is extensively metabolised and only traces are excreted unchanged in urine (Tucker & Mather 1979).Both cytochrome P450 (CYP) 3A4 and 1A2 isoenzymes can be important in the metabolism of lidocaine. The tissue distribution of CYP3A4 and 1A2 is different: CYP3A4 is extensively expressed in the gastrointestinal wall and liver whereas CYP1A2 is mainly located in the liver (Shimada et al. 1994;Kivistö et al. 1996). Accordingly, the relative role of CYP3A4 and 1A2 in lidocaine metabolism can depend on the route of its administration.It has been shown previously that fluvoxamine, a potent inhibitor of CYP1A2 (Brøsen et al. 1993;Rasmussen et al. 1995), considerably decreases the elimination of intravenous lidocaine (Orlando et al. 2004;Olkkola et al. 2005), whereas the strong inhibitors of CYP3A4 erythromycin and itraconazole have only a minor effect (Isohanni et al. 1998). The concomitant inhibition of CYP1A2 and CYP3A4 has affected the pharmacokinetics of intravenous lidocaine

Effect of erythromycin and rifampicin on monoethylglycinexylidide test

“…This study correlates well with other studies[14–16] concluding that the metabolism of lidocaine is based on both CYP1A2 and CYP3A4 isoforms rather than that of CYP3A4 alone.…”

Antiulcer activity of fluvoxamine in rats and its effect on oxidant and antioxidant parameters in stomach tissue

“…Fluvoxamine in doses of 25, 50, 100 or 200 mg/kg [35,36] and ranitidine in a 50-mg/kg dose were administered to 24-hour fasted rat groups by oral gavage. An equal volume of distilled water was administered to the control group as a vehicle.…”

Effect of an anesthesia with propofol compared with desflurane on free radical production and liver function after partial hepatectomy

“…Our results suggest an improvement of hepatic function with propofol, but this should be interpreted with caution. Similar unexpected increases in plasma MEGX concentration following lidocaine administration were described when the CYP 3A4 inhibitor erythromycin was administered, suggesting that erythromycin could inhibit the metabolism of MEGX [35][36][37]. Propofol is considered to be an inhibitor of CYP 3A4 activity [12,34].…”

“…We should have therefore observed a decrease in MEGX formation in the propofol group. Similar unexpected increases in plasma MEGX concentration following lidocaine administration were described when the CYP 3A4 inhibitor erythromycin was administered, suggesting that erythromycin could inhibit the metabolism of MEGX [35][36][37]. With regard to these observations, we cannot discard the hypothesis that, like erythromycin, propofol could also have inhibited the metabolism of MEGX.…”