Ota Tsuneyoshi, Shinotoh Hitoshi, Fukushi Kiyoshi, Kikuchi Tatsuya, Sato Koichi, Tanaka Noriko, Shimada Hitoshi, Hirano Shigeki, Miyoshi Michie, Arai Heii, Suhara Tetsuya, Irie Toshiaki
Department of Molecular Probe, Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan.
Clin Neuropharmacol. 2010 Mar-Apr;33(2):74-8. doi: 10.1097/WNF.0b013e3181c71be9.
Estimate the value of in vivo plasma IC50 of donepezil, the concentration of donepezil in plasma that inhibits brain acetylcholinesterase (AChE) activity by 50% at the steady-state conditions of donepezil between the plasma and the brain.
N-[C] methylpiperidin-4-yl acetate ([C]MP4A) positron emission tomography was performed in 16 patients with probable Alzheimer disease (AD) before and during the treatment of donepezil (5 mg/day) with a mean interval of 5.3 months. The plasma IC50 value of donepezil was estimated from plasma donepezil concentrations and cerebral cortical mean AChE inhibition rates measured by positron emission tomography, using one-parameter model.
Donepezil reduced AChE activity uniformly in the cerebral cortex compared with the baseline in each AD patient, and the mean reduction rate in the cerebral cortex was 34.6%. The donepezil concentrations in the plasma ranged from 18.5 to 43.9 ng/mL with a mean of 28.9 +/- 7.3 ng/mL. The plasma IC50 value was estimated to be 53.6 +/- 4.0 ng/mL.
Once the plasma IC50 of donepezil is determined, the brain AChE inhibition rate could be estimated from the plasma concentration of donepezil in each subject based on the plasma IC50. Now that the mean donepezil concentrations in the plasma, when the patients took 5 mg/day, remained 28.9 ng/mL, approximately half of the plasma IC50, higher dose of donepezil might provide further benefits for patients with AD. This technique can be also applied to measure the in vivo plasma IC50 of other cholinesterase inhibitors such as rivastigmine and galantamine.
估算多奈哌齐的体内血浆IC50值，即在多奈哌齐血浆与脑之间达到稳态时，血浆中抑制脑乙酰胆碱酯酶（AChE）活性50%的多奈哌齐浓度。
对16例可能患有阿尔茨海默病（AD）的患者在多奈哌齐治疗前（5mg/天）及治疗期间（平均间隔5.3个月）进行N-[C]甲基哌啶-4-基乙酸酯（[C]MP4A）正电子发射断层扫描。使用单参数模型，根据血浆多奈哌齐浓度和正电子发射断层扫描测量的大脑皮质平均AChE抑制率估算多奈哌齐的血浆IC50值。
与各AD患者的基线相比，多奈哌齐使大脑皮质中的AChE活性均匀降低，大脑皮质的平均降低率为34.6%。血浆中的多奈哌齐浓度范围为18.5至43.9 ng/mL，平均为28.9±7.3 ng/mL。血浆IC50值估计为53.6±4.0 ng/mL。
一旦确定多奈哌齐的血浆IC50，就可以根据每个受试者的血浆多奈哌齐浓度和血浆IC50估算脑AChE抑制率。鉴于患者服用5mg/天多奈哌齐时血浆中的平均浓度保持在28.9 ng/mL，约为血浆IC50的一半，更高剂量的多奈哌齐可能会为AD患者带来更多益处。该技术也可应用于测量其他胆碱酯酶抑制剂如卡巴拉汀和加兰他敏的体内血浆IC50。
