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

The roles of cytochrome P-450 (CYP) enzymes in the N-deethylation, i.e., fo rmation of monoethylglycinexylidide (MEGX), and 3-hydroxylation of lidocain e were studied with human liver microsomes and recombinant human CYP isofor ms. Both CYP1A2 and CYP3A4 were found to be capable of catalyzing the forma tion of MEGX and 3-OH-lidocaine. Lidocaine N-deethylation by liver microsom es was strongly inhibited by furafylline (by about 60%) and anti-CYP1A1/2 a ntibodies (>75%) at 5 mu M lidocaine, suggesting that CYP1A2 was the major isoform catalyzing lidocaine N-deethylation at low (therapeutically relevan t) lidocaine concentrations. Troleandomycin inhibited the N-deethylation of lidocaine by about 50% at 800 mu M lidocaine, suggesting that the role of CYP3A4 may be more important than that of CYP1A2 at high lidocaine concentr ations. Chemical inhibition and immunoinhibition studies also indicated tha t 3-OH-lidocaine formation was catalyzed almost exclusively by CYP1A2, CYP3 A4 playing only a minor role. Although the CYP2C9 inhibitor sulfaphenazole (100 mu M) inhibited MEGX formation by about 30%, recombinant human CYP2C9 showed very low catalytic activity, suggesting a negligible role for this e nzyme in lidocaine N-deethylation. Chemical inhibition studies indicated th at CYP2C19, CYP2D6, and CYP2E1 did not play significant roles in the metabo lism 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.