Dopamine transporter occupancies in the human brain induced by therapeutic doses of oral methylphenidate
Dopamine transporter occupancies in the human brain induced by therapeutic doses of oral methylphenidate
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DOI：
10.1176/ajp.155.10.1325
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发表时间：
1998-10-01
影响因子：
17.7
通讯作者：
Pappas, N
中科院分区：
文献类型：
--
作者：
Volkow, ND;Wang, GJ;Pappas, N
目的：哌甲酯在治疗注意力缺陷障碍中的治疗效果归因于其通过阻断多巴胺转运蛋白来增加多巴胺的突触浓度的能力。然而，治疗剂量的哌甲酯所达到的多巴胺转运蛋白阻断水平尚不清楚。这项研究首次测量了口服哌醋甲酯在人脑中的多巴胺转运蛋白占有率及其在大脑中的摄取率。方法：应用正电子发射断层扫描（PET）和[C-11]可卡因检测7名正常人口服不同剂量哌醋甲酯后多巴胺转运体的分布。此外，通过使用PET和经口胃管给药的[C-11]哌甲酯，在狒狒脑中测定了口服哌甲酯的药代动力学。结果如下：在给药后120分钟，口服哌甲酯对多巴胺转运蛋白产生剂量依赖性阻滞;平均值=12%（SD= 4%）（5 mg）、40%（SD=12%）（10 mg）、54%（SD=5%）（20 mg）、72%（SD=3%）（40 mg）和74%（SD=2%）（60 mg）。阻断50%多巴胺转运蛋白所需的口服哌甲酯的估计剂量相当于0.25 mg/kg。口服哌醋甲酯后60分钟才达到脑内峰浓度。结论：口服哌甲酯在阻断多巴胺转运蛋白方面非常有效，在治疗用的体重调整剂量（0.3至0.6 mg/kg）下，哌甲酯可能占据超过50%的多巴胺转运蛋白。口服哌甲酯在大脑中达到峰值脑摄取的时间与报告的达到峰值行为效应的时间过程一致。
Objective: The therapeutic effects of methylphenidate in the treatment of attention deficit disorder have been attributed to its ability to increase the synaptic concentration of dopamine by blocking the dopamine transporters. However, the levels of dopamine transporter blockade achieved by therapeutic doses of methylphenidate are not known. This study measured, for the first time, dopamine transporter occupancy by orally administered methylphenidate in the human brain and its rate of uptake in the brain. Method: Positron emission tomography (PET) and [C-11]cocaine were used to estimate dopamine transporter occupancies after different doses of oral methylphenidate in seven normal subjects (mean age=24 years, SD=7). In addition, the pharmacokinetics of oral methylphenidate were measured in the baboon brain through use of PET and [C-11]methylphenidate administered through an orogastric tube. Results: At 120 minutes after administration, oral methylphenidate produced a dose-dependent blockade of dopamine transporter; means=12% (SD= 4%) for 5 mg, 40% (SD=12%) for 10 mg, 54% (SD=5%) for 20 mg, 72% (SD=3%) for 40 mg, and 74% (SD=2%) for 60 mg. The estimated dose of oral methylphenidate required to block 50% of the dopamine transporter corresponded to 0.25 mg/kg. Oral methylphenidate did not reach peak concentration in brain until 60 minutes after its administration. Conclusions: Oral methylphenidate is very effective in blocking dopamine transporters, and at the weight-adjusted doses used therapeutically (0.3 to 0.6 mg/kg), it is likely to occupy more than 50% of the dopamine transporters. The time to reach peak brain uptake for oral methylphenidate in brain corresponds well with the reported time course to reach peak behavioral effects.