Giordana Salvi de Souza, Wanling Liu, Pascalle Mossel, Joost F. Somsen, Anna L. Bartels, Cristiane R. G. Furini, Adriaan A. Lammertsma, Charalampos Tsoumpas, Gert Luurtsema
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Tissue time-activity curves (TAC) were extracted using the Hammers maximum-probability atlas. Whole-blood TAC was derived from the internal carotid arteries, calibrated using manual arterial samples, and adjusted for the plasma-to-whole blood ratio and plasma parent fraction to obtain the image-derived input function. The volume of distribution (<i>V</i><sub>T</sub>) was estimated using a reversible two-tissue compartment model, yielding the parameter of interest. Statistical analysis revealed no significant differences in P-gp function between sexes, based on <i>V</i><sub>T</sub> values across various brain regions (Cohen's <i>d</i> < 0.2). Furthermore, the arterial blood concentration, plasma parent fraction, and microparameters demonstrated no statistical differences between male and female participants. These findings suggest that P-gp function at the BBB does not exhibit substantial sex-related variability in healthy older adults (55+). For future [<sup>18</sup>F]MC225 PET studies, a mixed-sex population can serve as an appropriate age-matched control group for neurodegenerative studies. Further research is needed to explore sex-related differences in younger populations, particularly with respect to hormonal cycles.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"18 4","pages":""},"PeriodicalIF":3.1000,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.70196","citationCount":"0","resultStr":"{\"title\":\"Exploratory Study of Sex Differences in P-Glycoprotein Function at the Blood–Brain Barrier\",\"authors\":\"Giordana Salvi de Souza, Wanling Liu, Pascalle Mossel, Joost F. Somsen, Anna L. Bartels, Cristiane R. G. Furini, Adriaan A. 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引用次数: 0
摘要
通透性糖蛋白(P-gp)是一种重要的外排泵转运蛋白,由ABCB1基因编码,在血脑屏障(BBB)的药物处置中起关键作用,并参与许多治疗药物的药代动力学。本研究使用[18F]MC225和PET研究老年(55岁以上)健康志愿者(HV)队列中男性和女性血脑屏障P-gp功能的差异。20例HV患者(11男9女),无影响P-gp功能的药物,无神经或精神疾病史,接受MC225 PET扫描和人工动脉采血[18F]。采用Hammers最大概率图谱提取组织时间-活性曲线(TAC)。全血TAC来源于颈内动脉,使用手动动脉样本进行校准,并根据血浆与全血比率和血浆母体分数进行调整,以获得图像衍生的输入函数。分布体积(VT)估计使用可逆的两组织室模型,产生感兴趣的参数。基于不同脑区的VT值,统计分析显示P-gp功能在性别之间没有显著差异(Cohen's d < 0.2)。此外,动脉血浓度、血浆母体分数和微参数在男性和女性参与者之间没有统计学差异。这些发现表明,在健康老年人(55岁以上)中,血脑屏障的P-gp功能没有明显的性别差异。在未来的[18F]MC225 PET研究中,混合性别人群可以作为神经退行性研究的合适年龄匹配的对照组。需要进一步的研究来探索年轻人群中与性别有关的差异,特别是在激素周期方面。
Exploratory Study of Sex Differences in P-Glycoprotein Function at the Blood–Brain Barrier
Permeability-glycoprotein (P-gp), a crucial efflux pump transporter encoded by the ABCB1 gene, plays a pivotal role in drug disposition at the blood–brain barrier (BBB) and is involved in the pharmacokinetics of numerous therapeutic agents. This study investigates differences in P-gp function at the BBB between males and females in a cohort of older (55+) healthy volunteers (HV) using [18F]MC225 and PET. Twenty HV (11 males and 9 females), free from medications that affect P-gp function and without a history of neurological or psychiatric disorders, underwent [18F]MC225 PET scans with manual arterial blood sampling. Tissue time-activity curves (TAC) were extracted using the Hammers maximum-probability atlas. Whole-blood TAC was derived from the internal carotid arteries, calibrated using manual arterial samples, and adjusted for the plasma-to-whole blood ratio and plasma parent fraction to obtain the image-derived input function. The volume of distribution (VT) was estimated using a reversible two-tissue compartment model, yielding the parameter of interest. Statistical analysis revealed no significant differences in P-gp function between sexes, based on VT values across various brain regions (Cohen's d < 0.2). Furthermore, the arterial blood concentration, plasma parent fraction, and microparameters demonstrated no statistical differences between male and female participants. These findings suggest that P-gp function at the BBB does not exhibit substantial sex-related variability in healthy older adults (55+). For future [18F]MC225 PET studies, a mixed-sex population can serve as an appropriate age-matched control group for neurodegenerative studies. Further research is needed to explore sex-related differences in younger populations, particularly with respect to hormonal cycles.
期刊介绍:
Clinical and Translational Science (CTS), an official journal of the American Society for Clinical Pharmacology and Therapeutics, highlights original translational medicine research that helps bridge laboratory discoveries with the diagnosis and treatment of human disease. Translational medicine is a multi-faceted discipline with a focus on translational therapeutics. In a broad sense, translational medicine bridges across the discovery, development, regulation, and utilization spectrum. Research may appear as Full Articles, Brief Reports, Commentaries, Phase Forwards (clinical trials), Reviews, or Tutorials. CTS also includes invited didactic content that covers the connections between clinical pharmacology and translational medicine. Best-in-class methodologies and best practices are also welcomed as Tutorials. These additional features provide context for research articles and facilitate understanding for a wide array of individuals interested in clinical and translational science. CTS welcomes high quality, scientifically sound, original manuscripts focused on clinical pharmacology and translational science, including animal, in vitro, in silico, and clinical studies supporting the breadth of drug discovery, development, regulation and clinical use of both traditional drugs and innovative modalities.