Pharmacokinetics of levodopa
Pharmacokinetics of levodopa
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DOI：
10.1007/s00415-010-5728-8
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发表时间：
2010-11-01
影响因子：
6
通讯作者：
Martinelli, Paolo
中科院分区：
文献类型：
--
作者：
Contin, Manuela;Martinelli, Paolo
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和主要观察到的左旋多巴浓度-效应关系与帕金森病（PD）进展的变化。简要讨论了优化左旋多巴药物代谢和药效学的临床实用策略。左旋多巴显示出特殊的药代动力学，包括广泛的系统前代谢，通过结合使用酶L-的脑外抑制剂来克服，氨基酸脱羧酶和通过与其他大的中性氨基酸共享的可饱和易化转运系统在近端小肠中的快速吸收药物从血浆到脑的转运由相同的载体介导在肠粘膜中起作用确保肠吸收和向脑递送的再现性以及临床效果的主要策略包括相对于进餐时间和受控的膳食蛋白质摄入的左旋多巴剂量的标准化。左旋多巴血浆半衰期非常短，导致显著的血浆药物浓度波动，随着疾病的进展，治疗反应的波动（“磨损”现象）“磨损”现象也可在更晚期的疾病阶段与“负”相关，即在低的、亚治疗血浆浓度下左旋多巴的帕金森病恶化和运动障碍作用。运动障碍也可与高左旋多巴有关，过高的血浆浓度单独在临床基础上识别不同的左旋多巴毒性反应模式可能很困难，同时监测左旋多巴浓度-效应关系可能被证明有助于揭示潜在机制和规划正确的管理优化左旋多巴药代动力学的临床实用策略，以及可能的治疗反应，包括液体药物溶液、控释制剂和左旋多巴代谢抑制剂的使用。不幸的是，由于伴随PD患者黑质纹状体多巴胺能系统的进行性变性的脑左旋多巴动力学的复杂改变，这些尝试迄今仅被证明部分成功。
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 phannacokinetics 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