Geldof Marian, Freijer Jan I, Peletier Lambertus A, van Beijsterveldt Ludy, Danhof Meindert
Division of Pharmacology, LACDR, Leiden University, P.O. Box 9502, 2300 RA Leiden, The Netherlands.
Eur J Pharm Sci. 2008 Mar 3;33(3):217-29. doi: 10.1016/j.ejps.2007.12.001. Epub 2007 Dec 7.
A mechanistic model is proposed to predict the time course of the concentrations of 5-HT and its metabolite 5-hydroxyindolacetic acid (5-HIAA) in rat frontal cortex following acute administration of SSRIs. In the model, SSRIs increase synaptic 5-HT concentrations by reversible blockade of the SERT in a direct concentration-dependent manner, while the 5-HT response is attenuated by negative feedback via 5-HT autoreceptors. In principle, the model allows for the description of oscillatory patterns in the time course of 5-HT and 5-HIAA concentrations in brain extracellular fluid. The model was applied in a pharmacokinetic-pharmacodynamic (PK/PD) investigation on the time course of the microdialysate 5-HT and 5-HIAA response in rat frontal cortex following a 30-min intravenous infusion of 3.7 and 7.3mg/kg fluvoxamine. Directly after administration of fluvoxamine, concentrations of 5-HT were increased to approximately 450-600% of baseline values while 5-HIAA concentrations were decreased. Thereafter 5-HT and 5-HIAA concentrations gradually returned to baseline values in 6-10h, respectively. The PK/PD analysis revealed that inhibition of 5-HT reuptake was directly related to the fluvoxamine concentration in plasma, with 50% inhibition of 5-HT reuptake occurring at a plasma concentration of 1.1ng/ml (EC50). The levels of 5-HT at which 50% of the inhibition of the 5-HT response was reached (IC50) amounted to 272% of baseline. The model was unable to capture the oscillatory patterns in the individual concentration time curves, which appeared to occur randomly. The proposed mechanistic model is the first step in modeling of complex neurotransmission processes. The model constitutes a useful basis for prediction of the time course of median 5-HT and 5-HIAA concentrations in the frontal cortex in behavioral pharmacology studies in vivo.
提出了一种机制模型，用于预测急性给予选择性5-羟色胺再摄取抑制剂（SSRI）后大鼠额叶皮质中5-羟色胺（5-HT）及其代谢物5-羟吲哚乙酸（5-HIAA）浓度的时间进程。在该模型中，SSRI通过直接浓度依赖性方式可逆性阻断5-羟色胺转运体（SERT）来增加突触5-HT浓度，而5-HT反应通过5-HT自身受体的负反馈而减弱。原则上，该模型能够描述脑细胞外液中5-HT和5-HIAA浓度时间进程中的振荡模式。该模型应用于一项药代动力学-药效学（PK/PD）研究，该研究针对静脉输注3.7和7.3mg/kg氟伏沙明30分钟后大鼠额叶皮质中微透析液5-HT和5-HIAA反应的时间进程。给予氟伏沙明后，5-HT浓度立即增加至基线值的约450 - 600%，而5-HIAA浓度降低。此后，5-HT和5-HIAA浓度分别在6 - 10小时内逐渐恢复至基线值。PK/PD分析表明，5-HT再摄取的抑制与血浆中氟伏沙明浓度直接相关，在血浆浓度为1.1ng/ml（半数有效浓度，EC50）时发生50%的5-HT再摄取抑制。达到5-HT反应50%抑制时的5-HT水平（半数抑制浓度，IC50）相当于基线的272%。该模型无法捕捉个体浓度时间曲线中的振荡模式，这些振荡模式似乎是随机出现的。所提出的机制模型是对复杂神经传递过程进行建模的第一步。该模型为体内行为药理学研究中预测额叶皮质中5-HT和5-HIAA中位浓度的时间进程提供了有用的基础。
