De Martin Sara, Orlando Rocco, Bertoli Massimo, Pegoraro Paola, Palatini Pietro
Department of Pharmacology, University of Padua, Padua, Italy.
Clin Pharmacol Ther. 2006 Dec;80(6):597-606. doi: 10.1016/j.clpt.2006.08.020.
The effect of chronic renal failure (CRF) on the pharmacokinetics of lidocaine, a drug cleared almost exclusively by hepatic metabolism, has thus far only been evaluated in patients undergoing regular hemodialysis. This study had 2 objectives: (1) to investigate the effect of CRF on the pharmacokinetics of lidocaine in both patients undergoing hemodialysis and patients not undergoing hemodialysis and (2) to test the effects of plasma from the patients examined and of lidocaine metabolites possibly accumulated in vivo on lidocaine biotransformation in vitro.
In a clinical investigation we studied the kinetics of lidocaine and its metabolites, monoethylglycinexylidide (MEGX) and glycinexylidide (GX), after intravenous injection of 1 mg/kg lidocaine in 15 healthy volunteers (creatinine clearance [CL(cr)] >80 mL/min x 1.73 m(-2)), 10 subjects with moderate renal insufficiency (CL(cr) between 30 and 60 mL/min x 1.73 m(-2)), 10 subjects with severe renal insufficiency (CL(cr) <30 mL/min x 1.73 m(-2)), and 10 functionally anephric patients undergoing long-term hemodialysis. In experiments in vitro we determined the effects of plasma and GX on the formation rate of the primary lidocaine metabolite, MEGX, by use of human liver microsomes.
In patients not undergoing hemodialysis, lidocaine kinetic parameters were altered in proportion to the degree of renal function impairment, but only in patients with severe renal insufficiency were differences statistically significant: clearance was about half that of control subjects (mean +/- SD, 6.01 +/- 2.54 mL/min x kg versus 11.87 +/- 2.97 mL/min x kg; P < .001), and half-life was approximately doubled (4.55 +/- 1.71 hours versus 2.24 +/- 0.55 hours, P < .001). No such alterations were observed in patients undergoing regular hemodialysis, whose values were similar to those of the control group. The steady-state volume of distribution and MEGX levels were independent of renal function, whereas GX levels were more than double those of control subjects (P < .05) in all CRF groups. No inhibitory effect of plasma was observed, for any of the subjects examined, on lidocaine biotransformation in vitro. GX was found to be a competitive inhibitor, but its apparent inhibition constant value (52 +/- 6 micromol/L) was 2 orders of magnitude higher than its concentrations in vivo.
Our in vivo findings have both clinical and methodologic implications: (1) Lidocaine dose adjustment may be required in patients with severe renal insufficiency who are not receiving hemodialysis. (2) Results of studies evaluating the effect of CRF on metabolic drug disposition are not of general validity, unless both patients undergoing hemodialysis and patients not undergoing hemodialysis have been examined. Our in vitro observations exclude that impairment of lidocaine disposition is the result of direct inhibition of metabolizing enzymes by accumulated metabolites or uremic toxins. Alternative mechanisms, suggested by the results of recent in vitro studies, are discussed.
慢性肾衰竭（CRF）对利多卡因药代动力学的影响，迄今仅在接受定期血液透析的患者中进行过评估，利多卡因几乎完全通过肝脏代谢清除。本研究有两个目的：（1）研究CRF对接受血液透析和未接受血液透析患者利多卡因药代动力学的影响；（2）测试所检查患者的血浆以及体内可能蓄积的利多卡因代谢产物对利多卡因体外生物转化的影响。
在一项临床研究中，我们在15名健康志愿者（肌酐清除率[CL(cr)]>80 mL/min×1.73 m(-2)）、10名中度肾功能不全患者（CL(cr)在30至60 mL/min×1.73 m(-2)之间）、10名重度肾功能不全患者（CL(cr)<30 mL/min×1.73 m(-2)）和10名接受长期血液透析的功能性无肾患者中，静脉注射1 mg/kg利多卡因后，研究了利多卡因及其代谢产物单乙基甘氨酰二甲苯酰胺（MEGX）和甘氨酰二甲苯酰胺（GX）的动力学。在体外实验中，我们用人肝微粒体测定了血浆和GX对主要利多卡因代谢产物MEGX形成速率的影响。
在未接受血液透析的患者中，利多卡因动力学参数随肾功能损害程度成比例改变，但仅在重度肾功能不全患者中差异有统计学意义：清除率约为对照组的一半（均值±标准差，6.01±2.54 mL/min×kg对11.87±2.97 mL/min×kg；P<.001），半衰期约增加一倍（4.55±1.71小时对2.24±0.55小时，P<.001）。在接受定期血液透析的患者中未观察到此类改变，其值与对照组相似。稳态分布容积和MEGX水平与肾功能无关，而在所有CRF组中，GX水平是对照组的两倍多（P<.05）。在所检查的任何受试者中，均未观察到血浆对利多卡因体外生物转化有抑制作用。发现GX是一种竞争性抑制剂，但其表观抑制常数（52±6 μmol/L）比其体内浓度高2个数量级。
我们的体内研究结果具有临床和方法学意义：（1）未接受血液透析的重度肾功能不全患者可能需要调整利多卡因剂量。（2）除非同时检查接受血液透析和未接受血液透析的患者，否则评估CRF对药物代谢处置影响的研究结果不具有普遍有效性。我们的体外观察排除了利多卡因处置受损是由蓄积代谢产物或尿毒症毒素直接抑制代谢酶所致。讨论了近期体外研究结果所提示的其他机制。
