Wang J S, Backman J T, Wen X, Taavitsainen P, Neuvonen P J, Kivistö K T
Department of Clinical Pharmacology, University of Helsinki and Helsinki University Central Hospital, Finland.
Pharmacol Toxicol. 1999 Nov;85(5):201-5. doi: 10.1111/j.1600-0773.1999.tb02009.x.
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.
一般认为，CYP3A4是参与利多卡因在人体生物转化的主要细胞色素P450（CYP）酶；然而，最近的体内研究表明情况可能并非如此。我们研究了CYP3A4抑制剂红霉素和酮康唑以及CYP1A2抑制剂氟伏沙明对人肝微粒体中利多卡因N - 去乙基化（即单乙基甘氨酰二甲苯酰胺（MEGX）的形成）和3 - 羟基化的影响。实验在利多卡因浓度为5微摩尔/升（临床相关浓度）和800微摩尔/升下进行。MEGX和3 - 羟基利多卡因的形成最好用双酶模型来描述。在5微摩尔/升的利多卡因浓度下，氟伏沙明是MEGX形成的强效抑制剂（半数抑制浓度（IC50）为1.2微摩尔/升）。酮康唑和红霉素对MEGX的形成也有抑制作用，但酮康唑（IC50为8.5微摩尔/升）比红霉素（IC50为200微摩尔/升）是更强效的抑制剂。在80微摩尔/升的利多卡因浓度下，氟伏沙明（IC50为20.7微摩尔/升）和酮康唑（IC50为20.4微摩尔/升）对MEGX的形成表现出适度的抑制作用，而红霉素是弱抑制剂（IC50＞250微摩尔/升）。在两种利多卡因浓度下，氟伏沙明均对利多卡因的3 - 羟基化有强效抑制作用（5微摩尔/升时IC50为0.16微摩尔/升，800微摩尔/升时为1.8微摩尔/升）。在5微摩尔/升的利多卡因浓度下，红霉素和酮康唑对利多卡因的3 - 羟基化有明显抑制作用（IC50分别为9.9微摩尔/升和13.9微摩尔/升），但在800微摩尔/升的利多卡因浓度下未表现出一致的作用（IC50分别＞250微摩尔/升和75.0微摩尔/升）。尽管需要进一步研究以阐明不同CYP酶在利多卡因人体生物转化中的作用，但本研究结果表明，虽然CYP1A2和CYP3A4均参与人肝微粒体中利多卡因的代谢，但在临床相关的利多卡因浓度下，CYP1A2是更重要的同工酶。
