Tam Y K, Yau M, Berzins R, Montgomery P R, Gray M
Drug Metab Dispos. 1987 Jan-Feb;15(1):12-6.
The mechanisms of time-related reduction in lidocaine clearance were studied using a "one-pass" perfused rat liver system. Lidocaine was infused continuously for a period up to 150 min (concentration ranged from 9.6 to 278 microM). The time required for lidocaine to achieve steady state in the effluent ranged from 20 to 90 min. Analysis of material balance suggested that capacity-limited tissue binding was partially responsible for determining the time to steady state. The characteristic rise of monoethylglycinexylidide to a maximum within 5 min and decline to a stable level during constant lidocaine infusion suggested that the deethylation pathway may be partly deactivated. This observation could be the major determinant for the time-dependent effects of lidocaine elimination. Saturation of metabolism, mainly hydroxylation, and product inhibition by monoethylglycinexylidide did not reduce the extraction of lidocaine significantly. The dose-related reduction in lidocaine elimination is believed to have little contribution to the time effects of lidocaine.
利用“单程”灌注大鼠肝脏系统研究了利多卡因清除率随时间降低的机制。持续输注利多卡因长达150分钟（浓度范围为9.6至278微摩尔/升）。利多卡因在流出液中达到稳态所需的时间为20至90分钟。物质平衡分析表明，容量受限的组织结合部分决定了达到稳态的时间。单乙基甘氨酰二甲苯在5分钟内升至最大值并在持续输注利多卡因期间降至稳定水平，这表明去乙基化途径可能部分失活。这一观察结果可能是利多卡因消除时间依赖性效应的主要决定因素。代谢饱和（主要是羟基化）以及单乙基甘氨酰二甲苯的产物抑制并未显著降低利多卡因的提取率。利多卡因消除的剂量相关降低被认为对利多卡因的时间效应贡献不大。
