Dietz M, Harder S, Graff J, Künig G, Vontobel P, Leenders K L, Baas H
Department of Neurology and the Institute for Clinical Pharmacology, University Hospital, Frankfurt am Main, Germany.
Clin Pharmacol Ther. 2001 Jul;70(1):33-41. doi: 10.1067/mcp.2001.116328.
Parameters of a pharmacokinetic-pharmacodynamic (PK-PD) model of levodopa have been claimed to reflect the magnitude of the dopaminergic deficit in patients with Parkinson's disease. The aim of this study was to correlate such parameters with positron emission tomography (PET) with levodopa tagged with 6-fluorine 18, an established imaging method for striatal dopaminergic neurons.
Twenty-three patients in different disease stages (Hoehm and Yahr stage 2.5-5 [Hoehn MM, Yahr MD. Parkinsonism: onset, progression and mortality. Neurology 1967;4:427-42]; median duration, 12 years) were studied. PK-PD modeling followed a single oral dose of levodopa/benserazide. The sum score of the Columbia Rating Scale (CURSSigma) was used for clinical assessments. A nonparametric effect compartment approach assuming a sigmoidal E(max) model was applied to the PK-PD analysis of plasma levodopa concentrations and corresponding CURSSigma. Thereafter 6-[18F]levodopa PET was performed, and the influx rate constants (k(c)) for the putamen and the caudatus region were correlated with the median effective concentration (EC(50)) and the equilibrium half-life (T(eq)) of the PK-PD model.
(1) A significant correlation was observed between PK-PD parameters or with k(c) putamen as the dependent variable and the duration of the disease as the independent variable, which explains 33% of the variability of the EC(50), 42% of the variability of T(eq), and 36% of the variability of k(c). (2) Significant correlations were observed between k(c) and either EC(50) or T(eq), yielding the closest correlation for the putamen region (r = -0.47, P <.05; and r = 0.55, P <.01; respectively).
Our findings show that key parameters of a PK-PD model of levodopa were in fairly close agreement with imaging of dopaminergic neurons by 6-[18F]levodopa PET. However, although PK-PD modeling of levodopa has been proven as a useful investigation of approaches aimed to restore dopaminergic deficits or to monitor disease progression, this modeling cannot serve as a pathomorphologic surrogate for the loss of striatal dopaminergic neurons.
左旋多巴药代动力学 - 药效学（PK - PD）模型的参数据称可反映帕金森病患者多巴胺能缺陷的程度。本研究的目的是将这些参数与用6 - 氟 - 18标记的左旋多巴正电子发射断层扫描（PET）相关联，这是一种用于纹状体多巴胺能神经元的既定成像方法。
对23例处于不同疾病阶段（Hoehm和Yahr分期2.5 - 5期[Hoehn MM, Yahr MD. Parkinsonism: onset, progression and mortality. Neurology 1967;4:427 - 42]; 中位病程12年）的患者进行了研究。PK - PD建模采用单次口服左旋多巴/苄丝肼。使用哥伦比亚评定量表总分（CURSSigma）进行临床评估。采用假设为S形E(max)模型的非参数效应室方法对血浆左旋多巴浓度和相应的CURSSigma进行PK - PD分析。此后进行6 - [18F]左旋多巴PET检查，并将壳核和尾状核区域的流入速率常数（k(c)）与PK - PD模型的中位有效浓度（EC(50)）和平衡半衰期（T(eq)）相关联。
（1）观察到以PK - PD参数或壳核k(c)为因变量、疾病持续时间为自变量之间存在显著相关性，这解释了EC(50)变异性的33%、T(eq)变异性的42%以及k(c)变异性的36%。（2）观察到k(c)与EC(50)或T(eq)之间存在显著相关性，壳核区域的相关性最为密切（分别为r = - 0.47，P <.05；r = 0.55，P <.01）。
我们的研究结果表明，左旋多巴PK - PD模型的关键参数与6 - [18F]左旋多巴PET对多巴胺能神经元的成像结果相当吻合。然而，尽管左旋多巴的PK - PD建模已被证明是一种用于恢复多巴胺能缺陷或监测疾病进展的有用研究方法，但这种建模不能作为纹状体多巴胺能神经元丢失的病理形态学替代指标。
