Olkkola Klaus T, Isohanni Mika H, Hamunen Katri, Neuvonen Pertti J
*Department of Anaesthesiology and Intensive Care, University of Turku, Turku, Finland; †Department of Anaesthesia, Deaconess Hospital, Helsinki, Finland; and the ‡Department of Clinical Pharmacology and §Department of Anaesthesiology and Intensive Care Medicine, University of Helsinki, Helsinki, Finland.
Anesth Analg. 2005 May;100(5):1352-1356. doi: 10.1213/01.ANE.0000148123.79437.F9.
Inhibitors of CYP3A4 (cytochrome P450 3A4) have a minor effect on lidocaine pharmacokinetics. We studied the effect of coadministration of the antidepressant fluvoxamine (CYP1A2 inhibitor) and antimicrobial drug erythromycin (CYP3A4 inhibitor) on lidocaine pharmacokinetics in a double-blind, randomized, three-way crossover study. Nine volunteers ingested daily 100 mg fluvoxamine and placebo, 100 mg fluvoxamine and 1500 mg erythromycin, or their corresponding placebos for 5 days. On day 6, 1.5 mg/kg lidocaine was administered IV over 60 min. Concentrations of lidocaine and its major metabolite monoethylglycinexylidide were measured for 10 h. Fluvoxamine alone decreased the clearance of lidocaine by 41% (P < 0.001) and prolonged its elimination half-life from 2.6 to 3.5 h (P < 0.01). During the combination of fluvoxamine and erythromycin, lidocaine clearance was 53% smaller than during placebo (P < 0.001) and 21% smaller than during fluvoxamine alone (P < 0.05). During the combination phase the half-life of lidocaine (4.3 h) was longer than during the placebo (2.6 h; P < 0.001) or fluvoxamine (3.5 h; P < 0.01). We conclude that inhibition of CYP1A2 by fluvoxamine considerably reduces elimination of lidocaine and may increase the risk of lidocaine toxicity. Concomitant use of both fluvoxamine and a CYP3A4 inhibitor such as erythromycin can further increase plasma lidocaine concentrations by decreasing its clearance.
细胞色素P450 3A4（CYP3A4）抑制剂对利多卡因的药代动力学影响较小。我们在一项双盲、随机、三交叉研究中，研究了抗抑郁药氟伏沙明（CYP1A2抑制剂）和抗菌药物红霉素（CYP3A4抑制剂）联合使用对利多卡因药代动力学的影响。9名志愿者每天服用100mg氟伏沙明和安慰剂、100mg氟伏沙明和1500mg红霉素或其相应的安慰剂，持续5天。在第6天，静脉输注1.5mg/kg利多卡因，持续60分钟。测定利多卡因及其主要代谢产物单乙基甘氨酰二甲苯酰胺的浓度，持续10小时。单独使用氟伏沙明可使利多卡因的清除率降低41%（P<0.001），并将其消除半衰期从2.6小时延长至3.5小时（P<0.01）。在氟伏沙明和红霉素联合使用期间，利多卡因的清除率比安慰剂组小53%（P<0.001），比单独使用氟伏沙明时小21%（P<0.05）。在联合使用阶段，利多卡因的半衰期（4.3小时）比安慰剂组（2.6小时；P<0.001）或氟伏沙明组（3.5小时；P<0.01）更长。我们得出结论，氟伏沙明对CYP1A2的抑制作用显著降低了利多卡因的消除，并可能增加利多卡因毒性的风险。氟伏沙明与CYP3A4抑制剂如红霉素同时使用，可通过降低其清除率进一步提高血浆利多卡因浓度。
