Division of Drug Delivery Technology, Leiden/Amsterdam Center for Drug Research, Leiden, The Netherlands.
J Pharm Sci. 2011 Jul;100(7):2996-3009. doi: 10.1002/jps.22492. Epub 2011 Jan 31.
The pharmacokinetic (PK) and pharmacodynamic (PD) properties of the active (S)-enantiomer of the potent dopamine (DA) agonist 5-hydroxy-2-(N,N,-di-n-propylamino)tetralin (5-OH-DPAT) were investigated in a novel anesthetized animal model. First, the relationship between current density, in vivo transport, and plasma profile was characterized. Second, the effect of the anesthetic mixture, transdermal iontophoresis, and blood sampling on the striatal DA release (PD end point) was investigated. Third, the PK-PD relationship following transdermal iontophoresis was investigated during a controlled reversible pharmacological response. Given that striatal DA levels are unaltered during experimental procedures, this rat model can be used to investigate the PK-PD relationship. The in vivo flux was linearly correlated with the current density, indicating that drug delivery can be titrated by the current density. Following transdermal iontophoresis and intravenous infusion, a strong reversible effect was observed. Compartmental modeling showed that the relationship between plasma concentration and biomarker response is best characterized by an effect compartment, rather than an indirect response model. In addition, covariate analysis suggested that the delivery rate can affect the PD efficiency. Finally, PK-PD analysis revealed that steady delivery rates are translated into continuous dopaminergic stimulation. This can be of benefit for reducing side effects in the symptomatic treatment of Parkinson's disease with 5-OH-DPAT.
在一种新型麻醉动物模型中，研究了强效多巴胺（DA）激动剂 5-羟基-2-（N，N-二正丙基氨基）四氢呋喃（5-OH-DPAT）的活性（S）-对映体的药代动力学（PK）和药效动力学（PD）特性。首先，表征了电流密度、体内转运和血浆谱之间的关系。其次，研究了麻醉混合物、透皮离子电渗和采血对纹状体 DA 释放（PD 终点）的影响。第三，在受控可逆药理反应期间研究了透皮离子电渗后的 PK-PD 关系。由于纹状体 DA 水平在实验过程中保持不变，因此可以使用这种大鼠模型来研究 PK-PD 关系。体内通量与电流密度呈线性相关，表明可以通过电流密度来滴定药物输送。透皮离子电渗和静脉输注后，观察到强烈的可逆作用。房室模型分析表明，血浆浓度与生物标志物反应之间的关系最好用效应室而不是间接反应模型来描述。此外，协变量分析表明，输送速率会影响 PD 效率。最后，PK-PD 分析表明，稳定的输送速率会转化为持续的多巴胺刺激。这对于减少使用 5-OH-DPAT 治疗帕金森病的症状性治疗中的副作用可能是有益的。
