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Pharmacokinetic Modeling of [18F]MC225 for Quantification of the P-Glycoprotein Function at the Blood-Brain Barrier in Non-Human Primates with PET.
Molecular Pharmaceutics ( IF 4.5 ) Pub Date : 2020-08-05 , DOI: 10.1021/acs.molpharmaceut.0c00514
Lara García-Varela 1 , Wejdan M Arif 1, 2 , David Vállez García 1 , Takeharu Kakiuchi 3 , Hiroyuki Ohba 3 , Norihiro Harada 3 , Tetsuro Tago 4 , Philip H Elsinga 1 , Hideo Tsukada 3 , Nicola Antonio Colabufo 5, 6 , Rudi A J O Dierckx 1 , Aren van Waarde 1 , Jun Toyohara 4 , Ronald Boellaard 1 , Gert Luurtsema 1
Affiliation  

[18F]MC225 has been developed as a weak substrate of P-glycoprotein (P-gp) aimed to measure changes in the P-gp function at the blood–brain barrier with positron emission tomography. This study evaluates [18F]MC225 kinetics in non-human primates and investigates the effect of both scan duration and P-gp inhibition. Three rhesus monkeys underwent two 91-min dynamic scans with blood sampling at baseline and after P-gp inhibition (8 mg/kg tariquidar). Data were analyzed using the 1-tissue compartment model (1-TCM) and 2-tissue compartment model (2-TCM) fits using metabolite-corrected plasma as the input function and for various scan durations (10, 20, 30, 60, and 91 min). The preferred model was chosen according to the Akaike information criterion and the standard errors (%) of the estimated parameters. For the 91-min scan duration, the influx constant K1 increased by 40.7% and the volume of distribution (VT) by 30.4% after P-gp inhibition, while the efflux constant k2 did not change significantly. Similar changes were found for all evaluated scan durations. K1 did not depend on scan duration (10 min—K1 = 0.2191 vs 91 min—K1 = 0.2258), while VT and k2 did. A scan duration of 10 min seems sufficient to properly evaluate the P-gp function using K1 obtained with 1-TCM. For the 91-min scan, VT and K1 can be estimated with a 2-TCM, and both parameters can be used to assess P-gp function.

中文翻译:

[18F] MC225的药代动力学模型,用于定量非人灵长类动物在PET时血脑屏障中的P-糖蛋白功能。

[ 18 F] MC225已开发为P-糖蛋白(P-gp)的弱底物,旨在通过正电子发射断层扫描技术测量血脑屏障处P-gp功能的变化。这项研究评估[ 18F] MC225在非人类灵长类动物体内的动力学,并研究了扫描时间和P-gp抑制作用。三只恒河猴在基线和抑制P-gp(8 mg / kg tariquidar)后进行了两次91分钟的动态扫描,并进行了血液采样。使用1组织隔室模型(1-TCM)和2组织隔室模型(2-TCM)拟合分析数据,使用代谢物校正血浆作为输入函数,并进行各种扫描时间(10、20、30、60,和91分钟)。根据Akaike信息准则和估计参数的标准误差(%)选择首选模型。在91分钟的扫描时间内,入流常数K 1增加了40.7%,分配量(V TP-gp抑制后)降低了30.4%,而流出常数k 2却没有显着变化。对于所有评估的扫描持续时间都发现了类似的变化。K 1不依赖于扫描持续时间(10分钟-K 1 = 0.2191 vs 91分钟-K 1 = 0.2258),而V Tk 2取决于。10分钟的扫描持续时间似乎足以使用1-TCM获得的K 1正确评估P-gp功能。对于91分钟的扫描,可以使用2-TCM估计V TK 1,并且两个参数都可以用于评估P-gp功能。
更新日期:2020-09-09
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