Relationship between Dose, Drug Levels, and D2 Receptor Occupancy for the Atypical Antipsychotics Risperidone and Paliperidone
Relationship between Dose, Drug Levels, and D2 Receptor Occupancy for the Atypical Antipsychotics Risperidone and Paliperidone
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DOI：
10.1124/jpet.111.189076
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发表时间：
2012-04-01
影响因子：
3.5
通讯作者：
Howell, L. L.
中科院分区：
文献类型：
--
作者：
Muly, E. C.;Votaw, J. R.;Howell, L. L.
D2家族多巴胺受体（D2 R）的阻断是抗精神病药物的基本特性，纹状体D2 R占用的程度与这些药物的抗精神病和运动效应有关。最近的研究表明，抗精神病药物的D2 R占用可能不同的纹状体外区域相比，背侧纹状体。我们研究了这个问题，在猕猴使用内科目设计。在四种不同剂量的利培酮和帕潘立酮（利培酮的9-OH代谢物）上获得[F-18] fallypride正电子发射断层扫描，并与每只动物的多次停药扫描进行比较。两种药物在这些猴中的半衰期测定为3 - 4 h，通过胃内导管持续输注给药。抗精神病药物的D2 R占用率在尾状核，壳核，腹侧纹状体，和四个前额和颞叶皮质区，并与血清和脑脊液药物水平。利培酮或帕潘立酮重复治疗2周，在检查的任何区域，D2 R结合电位均未产生持久变化。正如预期的那样，D2 R结合潜力是最高的尾状核和壳核，大约是三分之一的水平，在腹侧纹状体和2%的水平，在皮质区。我们发现利培酮和帕潘立酮在基底神经节和皮质感兴趣区域的剂量依赖性D2 R占有率。我们找不到任何一种药物的D2 R占用率存在区域差异的证据。D2 R结合率和血清药物水平的比较支持这两种非典型抗精神病药的活性药物目标为40 - 80 ng/ml。
Blockade of D2 family dopamine receptors (D2Rs) is a fundamental property of antipsychotics, and the degree of striatal D2R occupancy has been related to antipsychotic and motor effects of these drugs. Recent studies suggest the D2R occupancy of antipsychotics may differ in extrastriatal regions compared with the dorsal striatum. We studied this issue in macaque monkeys by using a within-subjects design. [F-18] fallypride positron emission tomography scans were obtained on four different doses of risperidone and paliperidone (the 9-OH metabolite of risperidone) and compared with multiple off-drug scans in each animal. The half-life of the two drugs in these monkeys was determined to be between 3 and 4 h, and drug was administered by a constant infusion through an intragastric catheter. The D2R occupancy of antipsychotic was determined in the caudate, putamen, ventral striatum, and four prefrontal and temporal cortical regions and was related to serum and cerebrospinal fluid drug levels. Repeated 2-week treatment with risperidone or paliperidone did not produce lasting changes in D2R binding potential in any region examined. As expected, D2R binding potential was highest in the caudate and putamen and was approximately one-third that level in the ventral striatum and 2% of that level in the cortical regions. We found dose-dependent D2R occupancy for both risperidone and paliperidone in both basal ganglia and cortical regions of interest. We could not find evidence of regional variation in D2R occupancy of either drug. Comparison of D2R occupancy and serum drug levels supports a target of 40 to 80 ng/ml active drug for these two atypical antipsychotics.