Biodistribution and metabolism of the anti-influenza drug [11C]oseltamivir and its active metabolite [11C]Ro 64-0802 in mice
Biodistribution and metabolism of the anti-influenza drug [11C]oseltamivir and its active metabolite [11C]Ro 64-0802 in mice
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DOI：
10.1016/j.nucmedbio.2008.10.008
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发表时间：
2009-01-01
影响因子：
3.1
通讯作者：
Zhang, Ming-Rong
中科院分区：
文献类型：
--
作者：
Hatori, Akiko;Arai, Takuya;Zhang, Ming-Rong
简介：磷酸奥司他韦（Tamiflu）是一种口服抗流感药物，其酯酶水解产物Ro 64-0802具有抑制流感病毒的活性。在日本，与使用奥司他韦相关的异常行为和死亡已经发展成为一个主要问题，达菲经常被用于季节性流感。确定人脑中奥司他韦和Ro 64-0802的量并阐明其量与神经精神副作用之间的关系至关重要。本研究的目的是评估[C-11]奥司他韦和[C-11]Ro 64-0802在小鼠体内作为有前途的正电子发射断层扫描（PET）配体用于测量它们在活体brain.Methods中的量：[C-11]奥司他韦和[C-11]Ro 64- 0802在小鼠体内的全身生物分布使用解剖方法和micro-PET。结果：注射[C-11]奥司他韦和[C-11]Ro 64-0802后1 ~ 60 min，在小鼠脑中分别检测到0.20- 0.06%ID/g和0.39- 0.03%ID/g（解剖法）。在[C-11]奥司他韦和[C-11]Ro 64-0802（micro-PET）的标准化摄取值分别为0.25-0.05和0.38-0.02时，测量注射后0 - 90 min活脑中的放射性浓度。结论：本研究确定了[C-11]奥司他韦和[C-11] Ro 64 - 0802在小鼠体内的分布和代谢。PET可以用来测量它们在活体大脑中的含量，并阐明大脑中的含量与达菲在中枢神经系统中的副作用之间的关系。(C)2009 Elsevier Inc. All rights reserved.
Introduction: Oseltamivir phosphate (Tamiflu) is ail orally active anti-influenza drug, which is hydrolyzed by esterase to its carboxylate metabolite Ro 64-0802 with potent activity to inhibit the influenza virus. The abnormal behavior and death associated with the use of oseltamivir have developed into a major problem in Japan where Tamiflu is often prescribed for seasonal influenza. It is critical to determine the amount of oseltamivir and Ro 64-0802 in the human brain and to elucidate the relationship between their amounts and neuropsychiatric side effects. The aim of this Study was to evaluate [C-11]oseltamivir and [C-11]Ro 64-0802 in mice as promising positron emission tomography (PET) ligands for Measuring their amounts in living brains.Methods: Whole-body biodistribution of [C-11]oseltamivir and [C-11]Ro 64-0802 was determined in mice using the dissection method and micro-PET. In vitro and in vivo metabolite assay was performed in the plasma and brain of mice.Results: Between 1 and 60 min after injection of [C-11]oseltamivir and [C-11]Ro 64-0802, 0.20-0.06% and 0.39-0.03% ID/g were detected in the mouse brains, respectively (dissection method). Radioactivity concentrations in the living brains between 0 and 90 min after injection were measured at standardized uptake values of 0.25-0.05 for [C-11]oseltamivir and 0.38-0.02 for [C-11]Ro 64-0802 (micro-PET). In vivo metabolite assay demonstrated the presence of [C-11]oseltamivir and [C-11]Ro 64-0802 in the brains after [C-11]oseltamivir injection.Conclusion: This Study determined the distribution and metabolism of [C-11]oseltamivir and [C-11]Ro 64-0802 in mice. PET could be used to measure their amounts in the living brain and to elucidate the relationship between the amounts in the brain and the side effects of Tamiflu in the central nervous system. (C) 2009 Elsevier Inc. All rights reserved.