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Drug Metab Dispos. 2000 Aug;28(8):959-65.

Involvement of CYP1A2 and CYP3A4 in lidocaine N-deethylation and 3-hydroxylation in humans.

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  • 1Department of Clinical Pharmacology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland.


The roles of cytochrome P-450 (CYP) enzymes in the N-deethylation, i.e., formation of monoethylglycinexylidide (MEGX), and 3-hydroxylation of lidocaine were studied with human liver microsomes and recombinant human CYP isoforms. Both CYP1A2 and CYP3A4 were found to be capable of catalyzing the formation of MEGX and 3-OH-lidocaine. Lidocaine N-deethylation by liver microsomes was strongly inhibited by furafylline (by about 60%) and anti-CYP1A1/2 antibodies (>75%) at 5 microM lidocaine, suggesting that CYP1A2 was the major isoform catalyzing lidocaine N-deethylation at low (therapeutically relevant) lidocaine concentrations. Troleandomycin inhibited the N-deethylation of lidocaine by about 50% at 800 microM lidocaine, suggesting that the role of CYP3A4 may be more important than that of CYP1A2 at high lidocaine concentrations. Chemical inhibition and immunoinhibition studies also indicated that 3-OH-lidocaine formation was catalyzed almost exclusively by CYP1A2, CYP3A4 playing only a minor role. Although the CYP2C9 inhibitor sulfaphenazole (100 microM) inhibited MEGX formation by about 30%, recombinant human CYP2C9 showed very low catalytic activity, suggesting a negligible role for this enzyme in lidocaine N-deethylation. Chemical inhibition studies indicated that CYP2C19, CYP2D6, and CYP2E1 did not play significant roles in the metabolism of lidocaine in vitro. Taken together, these results demonstrate that CYP1A2 and CYP3A4 enzymes are the major CYP isoforms involved in lidocaine N-deethylation. Therefore, the MEGX test (formation of MEGX from lidocaine) is not a suitable marker of hepatic CYP3A4 activity in vivo.

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