Fluvoxamine is a More Potent Inhibitor of Lidocaine Metabolism than Ketoconazole and Erythromycinin vitro

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Abstract
CYP3A4 is generally believed to be the major CYP enzyme involved in the biotransformation of lidocaine in man; however, recentin vivostudies 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 theN‐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 μM (clinically relevant concentration) and 800 μM. The formation of both MEGX and 3‐hydroxylidocaine was best described by a two‐enzyme model. At 5 μM of lidocaine, fluvoxamine was a potent inhibitor of the formation of MEGX (IC501.2 μM). Ketoconazole and erythromycin also showed an inhibitory effect on MEGX formation, but ketoconazole (IC508.5 μM) was a much more potent inhibitor than erythromycin (IC50200 μM). At 800 μM of lidocaine, fluvoxamine (IC5020.7 μM) and ketoconazole (IC5020.4 μM) displayed a modest inhibitory effect on MEGX formation, whereas erythromycin was a weak inhibitor (IC50>250 μM). The 3‐hydroxylation of lidocaine was potently inhibited by fluvoxamine at both lidocaine concentrations (IC500.16 μM at 5 μM and 1.8 μM at 800 μM). Erythromycin and ketoconazole showed a clear inhibitory effect on the 3‐hydroxylation of lidocaine at 5 μM of lidocaine (IC509.9 μM and 13.9 μM, respectively), but did not show a consistent effect at 800 μM of lidocaine (IC50>250 μM and 75.0 μM, 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.

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