Department of Neurological Sciences, Neurology Clinic, University of Bologna, Bologna, Italy.
J Neurol. 2010 Nov;257(Suppl 2):S253-61. doi: 10.1007/s00415-010-5728-8.
This paper reviews the clinically relevant determinants of levodopa peripheral pharmacokinetics and main observed changes in the levodopa concentration-effect relationship with Parkinson's disease (PD) progression. Available clinically practical strategies to optimise levodopa pharmacokinetics and pharmacodynamics are briefly discussed. Levodopa shows particular pharmacokinetics including an extensive presystemic metabolism, overcome by the combined use of extracerebral inhibitors of the enzyme L: -amino acid decarboxylase and rapid absorption in the proximal small bowel by a saturable facilitated transport system shared with other large neutral amino acids. Drug transport from plasma to the brain is mediated by the same carriers operating in the intestinal mucosa. The main strategies to assure reproducibility of both intestinal absorption and delivery to the brain, and the clinical effect include standardization of levodopa dosing with respect to meal times and a controlled dietary protein intake. Levodopa plasma half-life is very short, resulting in marked plasma drug concentration fluctuations which are matched, as the disease progresses, to swings in the therapeutic response ("wearing-off" phenomena). "Wearing-off" phenomena can also be associated, at the more advanced disease stages, with a "negative", both parkinsonism-exacerbating and dyskinetic effect of levodopa at low, subtherapeutic plasma concentrations. Dyskinesias may also be related to high-levodopa, excessive plasma concentrations. Recognition of the different levodopa toxic response patterns can be difficult on a clinical basis alone and simultaneous monitoring of the levodopa concentration-effect relationship may prove useful to disclose the underlying mechanism and in planning the correct management. Clinically practical strategies to optimise levodopa pharmacokinetics, and possibly its therapeutic response, include liquid drug solutions, controlled release formulations and the use of inhibitors of levodopa metabolism. Unfortunately, these attempts have proved so far only partly successful, due to the complex alterations in cerebral levodopa kinetics which accompany the progressive degeneration of the nigrostriatal dopaminergic system in PD patients.
本文综述了左旋多巴外周药代动力学的临床相关决定因素，以及帕金森病（PD）进展过程中观察到的左旋多巴浓度-效应关系的主要变化。简要讨论了优化左旋多巴药代动力学和药效学的临床实用策略。左旋多巴表现出特殊的药代动力学特性，包括广泛的前体药物代谢，通过联合使用脑外 L: -氨基酸脱羧酶抑制剂和与其他大中性氨基酸共享的近端小肠饱和易化转运系统来快速吸收。药物从血浆向大脑的转运是由在肠黏膜中起作用的相同载体介导的。确保肠道吸收和向大脑输送以及临床效果的重复性的主要策略包括根据进餐时间标准化左旋多巴剂量，并控制饮食中的蛋白质摄入量。左旋多巴的血浆半衰期非常短，导致其血浆药物浓度波动明显，随着疾病的进展，与治疗反应的波动（“开-关”现象）相匹配。“开-关”现象在疾病的更晚期阶段也可能与低治疗性血浆浓度下左旋多巴的“负”作用有关，即帕金森病恶化和运动障碍。运动障碍也可能与高剂量左旋多巴、血浆浓度过高有关。仅凭临床依据很难识别不同的左旋多巴毒性反应模式，同时监测左旋多巴的浓度-效应关系可能有助于揭示潜在的机制，并为正确的管理提供依据。优化左旋多巴药代动力学，可能还有其治疗反应的临床实用策略包括液体制剂、控释制剂和使用左旋多巴代谢抑制剂。不幸的是，由于 PD 患者黑质纹状体多巴胺能系统进行性退化引起的大脑左旋多巴动力学的复杂变化，这些尝试迄今为止仅取得部分成功。
