fluvoxamine and 3-hydroxylidocaine

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 (Cmax) 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 Cmax 250% (P<0.05) of those during placebo. Fluvoxamine alone had no statistically significant effect on the half-life of lidocaine (t1/2), but during the combination phase t1/2 (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.

Topics: Administration, Oral; Adult; Anesthetics, Local; Area Under Curve; Cross-Over Studies; Cytochrome P-450 CYP1A2 Inhibitors; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme Inhibitors; Dose-Response Relationship, Drug; Double-Blind Method; Enzyme Inhibitors; Erythromycin; Female; Fluvoxamine; Half-Life; Humans; Lidocaine; Male; Metabolic Clearance Rate; Nausea

CYP3A4 is generally believed to be the major CYP enzyme involved in the biotransformation of lidocaine in man; however, recent in vivo studies suggest that this may not be the case. We have examined the effects of the CYP3A4 inhibitors erythromycin and ketoconazole and the CYP1A2 inhibitor fluvoxamine on the N-deethylation, i.e. formation of monoethylglycinexylidide (MEGX), and 3-hydroxylation of lidocaine by human liver microsomes. The experiments were carried out at lidocaine concentrations of 5 microM (clinically relevant concentration) and 800 microM. The formation of both MEGX and 3-hydroxylidocaine was best described by a two-enzyme model. At 5 microM of lidocaine, fluvoxamine was a potent inhibitor of the formation of MEGX (IC50 1.2 microM). Ketoconazole and erythromycin also showed an inhibitory effect on MEGX formation, but ketoconazole (IC50 8.5 microM) was a much more potent inhibitor than erythromycin (IC50 200 microM). At 800 microM of lidocaine, fluvoxamine (IC50 20.7 microM) and ketoconazole (IC50 20.4 microM) displayed a modest inhibitory effect on MEGX formation, whereas erythromycin was a weak inhibitor (IC50 >250 microM). The 3-hydroxylation of lidocaine was potently inhibited by fluvoxamine at both lidocaine concentrations (IC50 0.16 microM at 5 microM and 1.8 microM at 800 microM). Erythromycin and ketoconazole showed a clear inhibitory effect on the 3-hydroxylation of lidocaine at 5 microM of lidocaine (IC50 9.9 microM and 13.9 microM, respectively), but did not show a consistent effect at 800 microM of lidocaine (IC50 >250 microM and 75.0 microM, respectively). Although further studies are needed to elucidate the role of distinct CYP enzymes in the biotransformation of lidocaine in humans, the findings of this study suggest that while both CYP1A2 and CYP3A4 are involved in the metabolism of lidocaine by human liver microsomes, CYP1A2 is the more important isoform at clinically relevant lidocaine concentrations.

Topics: Anesthetics, Local; Autopsy; Cytochrome P-450 CYP1A2 Inhibitors; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme Inhibitors; Dose-Response Relationship, Drug; Enzyme Inhibitors; Erythromycin; Fluvoxamine; Humans; In Vitro Techniques; Ketoconazole; Lidocaine; Male; Microsomes, Liver; Middle Aged; Mixed Function Oxygenases