静脉注射乙酰胆碱酯酶抑制剂及肾上腺中乙酰胆碱酯酶活性的分布：正常大鼠的11C-多奈哌齐PET研究

Distribution of intravenously administered acetylcholinesterase inhibitor and acetylcholinesterase activity in the adrenal gland: 11C-donepezil PET study in the normal rat.

作者信息

Watabe Tadashi, Naka Sadahiro, Ikeda Hayato, Horitsugi Genki, Kanai Yasukazu, Isohashi Kayako, Ishibashi Mana, Kato Hiroki, Shimosegawa Eku, Watabe Hiroshi, Hatazawa Jun

机构信息

Department of Molecular Imaging in Medicine, Osaka University Graduate School of Medicine, Suita, Osaka, Japan; PET molecular Imaging Center, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.

Osaka University Hospital, Suita, Osaka, Japan.

出版信息

PLoS One. 2014 Sep 16;9(9):e107427. doi: 10.1371/journal.pone.0107427. eCollection 2014.

DOI:10.1371/journal.pone.0107427

PMID:25225806

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC4166663/

Abstract

PURPOSE

Acetylcholinesterase (AChE) inhibitors have been used for patients with Alzheimer's disease. However, its pharmacokinetics in non-target organs other than the brain has not been clarified yet. The purpose of this study was to evaluate the relationship between the whole-body distribution of intravenously administered (11)C-Donepezil (DNP) and the AChE activity in the normal rat, with special focus on the adrenal glands.

METHODS

The distribution of (11)C-DNP was investigated by PET/CT in 6 normal male Wistar rats (8 weeks old, body weight = 220 ± 8.9 g). A 30-min dynamic scan was started simultaneously with an intravenous bolus injection of (11)C-DNP (45.0 ± 10.7 MBq). The whole-body distribution of the (11)C-DNP PET was evaluated based on the Vt (total distribution volume) by Logan-plot analysis. A fluorometric assay was performed to quantify the AChE activity in homogenized tissue solutions of the major organs.

RESULTS

The PET analysis using Vt showed that the adrenal glands had the 2nd highest level of (11)C-DNP in the body (following the liver) (13.33 ± 1.08 and 19.43 ± 1.29 ml/cm(3), respectively), indicating that the distribution of (11)C-DNP was the highest in the adrenal glands, except for that in the excretory organs. The AChE activity was the third highest in the adrenal glands (following the small intestine and the stomach) (24.9 ± 1.6, 83.1 ± 3.0, and 38.5 ± 8.1 mU/mg, respectively), indicating high activity of AChE in the adrenal glands.

CONCLUSIONS

We demonstrated the whole-body distribution of (11)C-DNP by PET and the AChE activity in the major organs by fluorometric assay in the normal rat. High accumulation of (11)C-DNP was observed in the adrenal glands, which suggested the risk of enhanced cholinergic synaptic transmission by the use of AChE inhibitors.

摘要

目的

乙酰胆碱酯酶（AChE）抑制剂已用于阿尔茨海默病患者。然而，其在大脑以外非靶器官中的药代动力学尚未明确。本研究的目的是评估静脉注射（11）C-多奈哌齐（DNP）在正常大鼠体内的全身分布与AChE活性之间的关系，特别关注肾上腺。

方法

通过PET/CT研究6只正常雄性Wistar大鼠（8周龄，体重=220±8.9 g）体内（11）C-DNP的分布。在静脉推注（11）C-DNP（45.0±10.7 MBq）的同时开始30分钟的动态扫描。基于Vt（总分布容积）通过Logan图分析评估（11）C-DNP PET的全身分布。进行荧光测定以量化主要器官匀浆组织溶液中的AChE活性。

结果

使用Vt的PET分析表明肾上腺是体内（11）C-DNP水平第二高的器官（仅次于肝脏）（分别为13.33±1.08和19.43±1.29 ml/cm³），表明（11）C-DNP在肾上腺中的分布除排泄器官外是最高的。AChE活性在肾上腺中排第三（仅次于小肠和胃）（分别为24.9±1.6、83.1±3.0和38.5±8.1 mU/mg），表明肾上腺中AChE活性较高。