Alfosea-Cuadrado Gloria M, Zarzoso-Foj Javier, Adell Albert, Valverde-Navarro Alfonso A, González-Soler Eva M, Mangas-Sanjuán Víctor, Blasco-Serra Arantxa
Department of Human Anatomy and Embryology, University of Valencia, 46010 Valencia, Spain.
Department of Pharmacy and Pharmaceutical Technology and Parasitology, University of Valencia, 46100 Valencia, Spain.
Pharmaceutics. 2024 Aug 21;16(8):1101. doi: 10.3390/pharmaceutics16081101.
(1) Background: Fibromyalgia syndrome (FMS) is a chronic pain condition with widespread pain and multiple comorbidities, for which conventional therapies offer limited benefits. The reserpine-induced myalgia (RIM) model is an efficient animal model of FMS in rodents. This study aimed to develop a pharmacokinetic-pharmacodynamic (PK-PD) model of reserpine in rats, linking to its impact on monoamines (MAs). (2) Methods: Reserpine was administered daily for three consecutive days at dose levels of 0.1, 0.5, and 1 mg/kg. A total of 120 rats were included, and 120 PK and 828 PD observations were collected from 48 to 96 h after the first dose of reserpine. Non-linear mixed-effect data analysis was applied for structural PK-PD model definition, variability characterization, and covariate analysis. (3) Results: A one-compartment model best described reserpine in rats (V = 1.3 mL/kg and CL = 4.5 × 10 mL/h/kg). A precursor-pool PK-PD model (k = 6.1 × 10 mg/h, k = 8.6 × 10 h and k = 2.7 × 10 h) with a parallel transit chain (k = 1.9 × 10 h) characterized the longitudinal levels of MA in the prefrontal cortex, spinal cord, and amygdala in rats. Reserpine stimulates the degradation of MA from the pool compartment (Slope = 1.1 × 10 h) and the elimination of MA (Slope = 1.25 h) through the transit chain. Regarding the reference dose (1 mg/kg) of the RIM model, the administration of 4 mg/kg would lead to a mean reduction of 65% (C), 80% (C), and 70% (AUC) of MA across the brain regions tested. (4) Conclusions: Regional brain variations in neurotransmitter depletion were identified, particularly in the amygdala, offering insights for therapeutic strategies and biomarker identification in FMS research.
(1) 背景：纤维肌痛综合征（FMS）是一种伴有广泛疼痛和多种合并症的慢性疼痛病症，传统疗法对其疗效有限。利血平诱导的肌痛（RIM）模型是啮齿动物中一种有效的FMS动物模型。本研究旨在建立利血平在大鼠体内的药代动力学 - 药效学（PK - PD）模型，并将其与对单胺类物质（MAs）的影响联系起来。(2) 方法：连续三天每天以0.1、0.5和1 mg/kg的剂量水平给予利血平。共纳入120只大鼠，在首次给予利血平后48至96小时收集了120个药代动力学和828个药效学观察数据。应用非线性混合效应数据分析来定义结构PK - PD模型、表征变异性并进行协变量分析。(3) 结果：单室模型能最好地描述利血平在大鼠体内的情况（V = 1.3 mL/kg，CL = 4.5×10 mL/h/kg）。一个具有平行转运链（k = 1.9×10 h）的前体池PK - PD模型（k = 6.1×10 mg/h，k = 8.6×10 h，k = 2.7×10 h）表征了大鼠前额叶皮质、脊髓和杏仁核中单胺类物质的纵向水平。利血平刺激单胺类物质从前体池隔室降解（斜率 = 1.1×10 h），并通过转运链消除单胺类物质（斜率 = 1.25 h）。关于RIM模型的参考剂量（1 mg/kg），给予4 mg/kg将导致所测试脑区中单胺类物质的平均减少量分别为65%（C）、80%（C）和70%（AUC）。(4) 结论：确定了神经递质耗竭在脑区的差异，特别是在杏仁核，这为FMS研究中的治疗策略和生物标志物识别提供了见解。
