Preclinical Molecular Imaging, AIT Austrian Institute of Technology GmbH, 2444 Seibersdorf, Austria.
Neuropharmacology, QPS Austria GmbH, Grambach, Austria.
Nucl Med Biol. 2020 May-Jun;84-85:28-32. doi: 10.1016/j.nucmedbio.2020.01.001. Epub 2020 Jan 13.
Tau deposition is one of the hallmarks of Alzheimer's disease (AD) and can be visualized and quantified using [F]THK-5317 together with kinetic modeling. To determine the feasibility of this approach, we measured blood/plasma pharmacokinetics and radiotracer metabolism in female and male rats.
Female and male rats (n = 11-12) were cannulated via the femoral artery for continuous blood sampling. Blood sampling was performed at regular intervals after intravenous injection of [F]THK-5317. After collection of the last blood sample, animals were sacrificed, and organs were excised. Blood from minute 5, 20 and 60 was centrifuged to obtain plasma. Radiolabeled metabolites in plasma, brain, liver and urine were analyzed by radio-thin-layer chromatography (radio-TLC).
Plasma pharmacokinetics and metabolism were significantly different between female and male rats. [F]THK-5317 plasma clearance was faster in female (0.66 ± 0.08 mL/h/kg BW) than in male (0.52 ± 0.11 mL/h/kg BW) rats (p = .005). The percentage of unmetabolized parent was significantly different between both sexes at 20 min and 60 min p.i. In the liver, a 1.6-fold higher radioactivity concentration was found in male versus female animals and in addition also the percentage of unmetabolized parent was different.
Our results show pronounced sex differences in blood/plasma pharmacokinetics and metabolism of [F]THK-5317 in rats. Female animals showed a faster plasma clearance compared to males. These results underline the importance of investigating both sexes and also support the notion that individual input functions or sex-specific population-based input functions are needed for kinetic modeling analyses.
First preclinical study in rats showing pronounced sex differences in blood/plasma pharmacokinetics and metabolism of [F]THK-5317.
Sex-specific differences might also be present in humans and thus clinical trials should have adequate sample size to account for effects in men and women separately.
tau 沉积是阿尔茨海默病（AD）的标志之一，可以使用 [F]THK-5317 结合动力学模型进行可视化和定量。为了确定这种方法的可行性，我们测量了雌性和雄性大鼠的血液/血浆药代动力学和示踪剂代谢。
通过股动脉对雌性和雄性大鼠（n=11-12）进行套管，以便连续采血。静脉注射 [F]THK-5317 后，每隔一定时间进行采血。采集最后一次血样后，处死动物并取出器官。从第 5、20 和 60 分钟采集的血液离心以获得血浆。通过放射性薄层层析（radio-TLC）分析血浆、脑、肝和尿中的放射性标记代谢物。
雌性和雄性大鼠的血浆药代动力学和代谢有显著差异。[F]THK-5317 血浆清除率在雌性（0.66±0.08 mL/h/kg BW）比雄性（0.52±0.11 mL/h/kg BW）更快（p=0.005）。在 20 分钟和 60 分钟时，两种性别之间未代谢的母体百分比有显著差异。在肝脏中，雄性动物的放射性浓度比雌性动物高 1.6 倍，并且未代谢的母体百分比也不同。
我们的结果表明，[F]THK-5317 在大鼠中的血液/血浆药代动力学和代谢存在明显的性别差异。与雄性相比，雌性动物的血浆清除率更快。这些结果强调了研究两性的重要性，并支持了需要为动力学建模分析提供个体输入函数或基于性别的群体输入函数的观点。
首次在大鼠中进行的临床前研究表明，[F]THK-5317 的血液/血浆药代动力学和代谢存在明显的性别差异。
性别差异也可能存在于人类中，因此临床试验应具有足够的样本量，以分别考虑男性和女性的影响。
