Toronto Western Research Institute, University Health Network, 399 Bathurst Street, Toronto, Ontario M5T 2S8, Canada.
Neuropharmacology. 2012 Oct;63(5):829-36. doi: 10.1016/j.neuropharm.2012.06.012. Epub 2012 Jun 18.
The 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned non-human primate is widely used to model Parkinson's disease (PD) and to evaluate the efficacy of new therapies. However, some doubts have been raised about the translatability of findings in the MPTP-lesioned monkey, because the doses of L-3,4-dihydroxyphenylalanine (L-DOPA) required to alleviate parkinsonism and elicit dyskinesia are high, on a mg/kg basis, when compared to clinical practice. Thus, in the MPTP-lesioned macaque, doses ranging from 20 to 40 mg/kg might be used, while in the clinic single L-DOPA administrations ranging from 100 to 200 mg are more typical. However, bioavailability of drugs varies between species and it is unknown how plasma L-DOPA levels providing therapeutic benefit in the non-human primate compare to those having similar actions in PD patients.
We administered acute challenges of L-DOPA 30 mg/kg orally to MPTP-lesioned macaques with established dyskinesia, and determined plasma, brain and cerebrospinal fluid (CSF) levels of L-DOPA using high-performance liquid chromatography-mass spectrometry/mass spectrometry.
The maximal plasma concentration of L-DOPA (C(max)) was 18.2 ± 3.8 nmol/ml and was achieved 1.6 ± 0.3 h after administration (t(max)). Half-life was 58.8 ± 22.7 min. L-DOPA levels in the caudate nucleus at peak behavioural effect were 3.3 ± 0.7 μg/g tissue protein while they were 1.5 ± 0.1 nmol/ml in the CSF.
Although therapeutically-active doses of L-DOPA administered to the MPTP-lesioned macaque are higher on a mg/kg basis than those administered in clinical settings, they lead to L-DOPA C(max) similar to those achieved with 200 mg L-DOPA in clinic. L-DOPA t(max) and half-life are also similar to those reported in human.
1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）损伤的非人灵长类动物被广泛用于帕金森病（PD）的模型，并评估新疗法的疗效。然而，有人对 MPTP 损伤猴的研究结果的可转移性提出了一些质疑，因为与临床实践相比，需要较高剂量的 L-3,4-二羟基苯丙氨酸（L-DOPA）来缓解帕金森病并引发运动障碍，以毫克/千克为单位。因此，在 MPTP 损伤的猕猴中，可能使用 20 至 40 毫克/千克的剂量，而在临床上，单次 L-DOPA 给药的范围从 100 到 200 毫克更为典型。然而，药物的生物利用度在不同物种之间存在差异，目前尚不清楚在非人类灵长类动物中提供治疗益处的血浆 L-DOPA 水平与在 PD 患者中具有相似作用的水平相比如何。
我们给患有已确立运动障碍的 MPTP 损伤猕猴口服急性 L-DOPA 30 毫克/千克挑战，并使用高效液相色谱-质谱/质谱法测定血浆、大脑和脑脊液（CSF）中的 L-DOPA 水平。
L-DOPA 的最大血浆浓度（C(max)）为 18.2±3.8 nmol/ml，在给药后 1.6±0.3 小时达到（t(max)）。半衰期为 58.8±22.7 分钟。在行为效应峰值时，纹状体核的 L-DOPA 水平为 3.3±0.7 μg/g 组织蛋白，而 CSF 中的 L-DOPA 水平为 1.5±0.1 nmol/ml。
虽然给予 MPTP 损伤猕猴的治疗有效剂量的 L-DOPA 以毫克/千克为单位比在临床环境中给予的剂量高，但它们导致的 L-DOPA C(max)与临床给予 200 mg L-DOPA 时相似。L-DOPA 的 t(max)和半衰期也与人类报道的相似。
