Moriguchi Sho, Takano Harumasa, Kimura Yasuyuki, Nagashima Tomohisa, Takahata Keisuke, Kubota Manabu, Kitamura Soichiro, Ishii Tatsuya, Ichise Masanori, Zhang Ming-Rong, Shimada Hitoshi, Mimura Masaru, Meyer Jeffrey H, Higuchi Makoto, Suhara Tetsuya
Department of Functional Brain Imaging Research, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan; Department of Neuropsychiatry, Keio University School of Medicine, Tokyo, Japan; Research Imaging Centre, Centre for Addiction and Mental Health, Toronto, Canada; Department of Psychiatry, National Center of Neurology and Psychiatry, Tokyo, Japan; Department of Clinical and Experimental Neuroimaging, Center for Development of Advanced Medicine for Dementia, National Center for Geriatrics and Gerontology, Obu, Japan.
Int J Neuropsychopharmacol. 2017 Dec 1;20(12):957-962. doi: 10.1093/ijnp/pyx069.
The norepinephrine transporter in the brain has been targeted in the treatment of psychiatric disorders. Duloxetine is a serotonin and norepinephrine reuptake inhibitor that has been widely used for the treatment of depression. However, the relationship between dose and plasma concentration of duloxetine and norepinephrine transporter occupancy in the human brain has not been determined. In this study, we examined norepinephrine transporter occupancy by different doses of duloxetine.
We calculated norepinephrine transporter occupancies from 2 positron emission tomography scans using (S,S)-[18F]FMeNER-D2 before and after a single oral dose of duloxetine (20 mg, n = 3; 40 mg, n = 3; 60 mg, n =2). Positron emission tomography scans were performed from 120 to 180 minutes after an i.v. bolus injection of (S,S)-[18F]FMeNER-D2. Venous blood samples were taken to measure the plasma concentration of duloxetine just before and after the second positron emission tomography scan.
Norepinephrine transporter occupancy by duloxetine was 29.7% at 20 mg, 30.5% at 40 mg, and 40.0% at 60 mg. The estimated dose of duloxetine inducing 50% norepinephrine transporter occupancy was 76.8 mg, and the estimated plasma drug concentration inducing 50% norepinephrine transporter occupancy was 58.0 ng/mL.
Norepinephrine transporter occupancy by clinical doses of duloxetine was approximately 30% to 40% in human brain as estimated using positron emission tomography with (S,S)-[18F]FMeNER-D2.
大脑中的去甲肾上腺素转运体已成为精神疾病治疗的靶点。度洛西汀是一种5-羟色胺和去甲肾上腺素再摄取抑制剂，已被广泛用于治疗抑郁症。然而，度洛西汀的剂量与血浆浓度以及其在人脑内对去甲肾上腺素转运体占有率之间的关系尚未明确。在本研究中，我们检测了不同剂量度洛西汀对去甲肾上腺素转运体的占有率。
在单次口服度洛西汀（20mg，n = 3；40mg，n = 3；60mg，n = 2）前后，使用(S,S)-[18F]FMeNER-D2通过两次正电子发射断层扫描计算去甲肾上腺素转运体占有率。在静脉推注(S,S)-[18F]FMeNER-D2后120至180分钟进行正电子发射断层扫描。在第二次正电子发射断层扫描前后采集静脉血样，以测量度洛西汀的血浆浓度。
度洛西汀在20mg时对去甲肾上腺素转运体的占有率为29.7%，40mg时为30.5%，60mg时为40.0%。诱导50%去甲肾上腺素转运体占有率的度洛西汀估计剂量为76.8mg，诱导50%去甲肾上腺素转运体占有率的估计血浆药物浓度为58.0ng/mL。
使用(S,S)-[18F]FMeNER-D2进行正电子发射断层扫描估计，临床剂量的度洛西汀在人脑中对去甲肾上腺素转运体的占有率约为30%至40%。
