Department of Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center Groningen, Hanzeplein 1, P.O. Box 30001, 9713 GZ Groningen, the Netherlands; Department of Nuclear Medicine and Molecular Imaging Group, Clinical University Hospital, IDIS Health Research Institute, s/n A, Travesía da Choupana, 15706 Santiago de Compostela, Spain.
Department of Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center Groningen, Hanzeplein 1, P.O. Box 30001, 9713 GZ Groningen, the Netherlands.
J Control Release. 2022 Jul;347:500-507. doi: 10.1016/j.jconrel.2022.05.026. Epub 2022 May 20.
The Blood-Brain Barrier P-glycoprotein (P-gp) function can be altered in several neurodegenerative diseases and due to the administration of different drugs which may cause alterations in drug concentrations and consequently lead to a reduced effectiveness or increased side-effects. The novel PET radiotracer [F]MC225 is a weak P-gp substrate that may show higher sensitivity to detect small changes in P-gp function than previously developed radiotracers. This study explores the sensitivity of [F]MC225 to measure the dose-dependent effect of P-gp inhibitor tariquidar. Twenty-three rats were intravenously injected with different doses of tariquidar ranging from 0.75 to 12 mg/kg, 30-min before the dynamic [F]MC225-PET acquisition with arterial sampling. Tissue and blood data were fitted to a 1-Tissue-Compartment-Model to obtain influx constant K and distribution volume V, which allow the estimation of P-gp function. ANOVA and post-hoc analyses of K values showed significant differences between controls and groups with tariquidar doses >3 mg/kg; while applying V the analyses showed significant differences between controls and groups with tariquidar doses >6 mg/kg. Dose-response curves were fitted using different models. The four-parameter logistic sigmoidal curve provided the best fit for K and V data. Half-maximal inhibitory doses (ID) were 2.23 mg/kg (95%CI: 1.669-2.783) and 2.93 mg/kg (95%CI: 1.135-3.651), calculated with K or V values respectively. According to the dose-response fit, differences in [F]MC225-K values could be detected at tariquidar doses ranging from 1.37 to 3.25 mg/kg. Our findings showed that small changes in the P-gp function, caused by low doses of tariquidar, could be detected by [F]MC225-K values, which confirms the high sensitivity of the radiotracer. The results suggest that [F]MC225 may allow the quantification of moderate P-gp impairments, which may allow the detection of P-gp dysfunctions at the early stages of a disease and potential transporter-mediated drug-drug interactions.
血脑屏障 P-糖蛋白（P-gp）的功能可在多种神经退行性疾病中发生改变，并且由于不同药物的给药可能导致药物浓度的改变，从而导致药物疗效降低或副作用增加。新型 PET 示踪剂[F]MC225 是一种弱 P-gp 底物，与以前开发的示踪剂相比，它可能对检测 P-gp 功能的微小变化具有更高的敏感性。本研究探讨了[F]MC225 测量 P-gp 抑制剂 tariquidar 剂量依赖性效应的灵敏度。23 只大鼠静脉注射不同剂量的 tariquidar，范围从 0.75 至 12mg/kg，在动态[F]MC225-PET 采集前 30 分钟进行，同时进行动脉取样。组织和血液数据拟合到 1 组织室模型，以获得摄取常数 K 和分布容积 V，从而可以估计 P-gp 功能。K 值的 ANOVA 和事后分析显示，tariquidar 剂量>3mg/kg 的各组与对照组之间存在显著差异；而应用 V 时，分析显示 tariquidar 剂量>6mg/kg 的各组与对照组之间存在显著差异。使用不同的模型拟合剂量反应曲线。四参数逻辑 sigmoidal 曲线为 K 和 V 数据提供了最佳拟合。半最大抑制剂量（ID）分别为 2.23mg/kg（95%CI：1.669-2.783）和 2.93mg/kg（95%CI：1.135-3.651），分别用 K 或 V 值计算。根据剂量反应拟合，tariquidar 剂量在 1.37 至 3.25mg/kg 范围内，[F]MC225-K 值的差异可被检测到。我们的研究结果表明，低剂量 tariquidar 引起的 P-gp 功能的微小变化可通过[F]MC225-K 值检测到，这证实了示踪剂的高灵敏度。结果表明，[F]MC225 可能允许量化中度 P-gp 损伤，这可能允许在疾病的早期阶段检测 P-gp 功能障碍，并可能检测到转运蛋白介导的药物-药物相互作用。
