Orlando Rocco, Piccoli Pierpaolo, De Martin Sara, Padrini Roberto, Floreani Maura, Palatini Pietro
Department of Medical and Sugical Sciences, University of Padua, Italy.
Clin Pharmacol Ther. 2004 Jan;75(1):80-8. doi: 10.1016/j.clpt.2003.09.007.
This study was designed (1) to evaluate the effect of a cytochrome P450 (CYP) 1A2 inhibitor, fluvoxamine, on the pharmacokinetics of intravenous lidocaine and its 2 pharmacologically active metabolites, monoethylglycinexylidide (MEGX) and glycinexylidide (GX), to confirm recent in vitro results indicating that CYP1A2 is the main isoform responsible for lidocaine biotransformation and (2) to assess whether liver function has any influence on the fluvoxamine-lidocaine interaction.
The study was carried out in 10 healthy volunteers and 20 patients with cirrhosis, 10 with mild (Child grade A) and 10 with severe (Child grade C) liver dysfunction, according to a randomized, double-blind, 2-phase, crossover design. In one phase all participants received placebo for 6 days; in the other phase they received 50 mg fluvoxamine for 2 days and 100 mg fluvoxamine for the next 4 days. On day 6, a 1-mg/kg lidocaine dose was administered intravenously 2 hours after the last dose of fluvoxamine or placebo. Plasma concentrations of lidocaine, MEGX, GX, and fluvoxamine were measured up to 12 hours after lidocaine injection.
The effects of fluvoxamine coadministration were dependent on liver function. Lidocaine clearance was decreased on average by 60% (from 12.1 mL/min.kg to 4.85 mL/min.kg, P <.001) in healthy subjects and by 44% (from 9.83 mL/min.kg to 5.06 mL/min.kg, P <.001) in patients with mild liver dysfunction, with proportional increases in terminal half-lives, whereas virtually no effect was produced in patients with severe liver dysfunction (4.21 mL/min.kg versus 3.65 mL/min.kg, P >.05). Analogous effects were observed on MEGX and GX formation kinetics, which were drastically impaired in healthy subjects and patients with mild liver cirrhosis but virtually unaffected in patients with severe cirrhosis.
CYP1A2 is the enzyme principally responsible for the metabolic disposition of lidocaine in subjects with normal liver function. The extent of fluvoxamine-lidocaine interaction decreases as liver function worsens, most likely because of the concomitant decrease in the hepatic level of CYP1A2. These observations indicate that results obtained in healthy subjects cannot be extended a priori to patients with liver dysfunction, but the clinical consequences of inhibition of drug metabolism must also be assessed in such patients.
本研究旨在（1）评估细胞色素P450（CYP）1A2抑制剂氟伏沙明对静脉注射利多卡因及其两种药理活性代谢物单乙基甘氨酰二甲苯胺（MEGX）和甘氨酰二甲苯胺（GX）药代动力学的影响，以证实最近的体外研究结果，即CYP1A2是负责利多卡因生物转化的主要同工酶；（2）评估肝功能是否对氟伏沙明-利多卡因相互作用有任何影响。
本研究根据随机、双盲、两阶段、交叉设计，在10名健康志愿者和20名肝硬化患者中进行，其中10名轻度（Child A级）和10名重度（Child C级）肝功能不全患者。在一个阶段，所有参与者接受6天的安慰剂；在另一个阶段，他们接受2天50mg氟伏沙明，接下来4天接受100mg氟伏沙明。在第6天，在最后一剂氟伏沙明或安慰剂后2小时静脉注射1mg/kg利多卡因剂量。在利多卡因注射后长达12小时测量利多卡因、MEGX、GX和氟伏沙明的血浆浓度。
氟伏沙明联合给药的效果取决于肝功能。健康受试者中利多卡因清除率平均降低60%（从12.1mL/min·kg降至4.85mL/min·kg，P<.001），轻度肝功能不全患者中降低44%（从9.83mL/min·kg降至5.06mL/min·kg，P<.001），终末半衰期成比例增加，而重度肝功能不全患者几乎没有影响（4.21mL/min·kg对3.65mL/min·kg，P>.05）。在MEGX和GX形成动力学上观察到类似的效果，在健康受试者和轻度肝硬化患者中显著受损，但在重度肝硬化患者中几乎未受影响。
CYP1A2是肝功能正常受试者中利多卡因代谢处置的主要酶。氟伏沙明-利多卡因相互作用的程度随着肝功能恶化而降低，最可能是因为CYP1A2肝脏水平同时降低。这些观察结果表明，在健康受试者中获得的结果不能先验地推广到肝功能不全患者，但在这类患者中也必须评估药物代谢抑制的临床后果。
