Gorin Boris I, Tukhovskaya Elena A, Ismailova Alina M, Slashcheva Gulsara A, Lenina Oksana A, Petrov Konstantin A, Kazeev Ilya V, Murashev Arkady N
Bigespas Ltd, London, United Kingdom.
Biological Testing Laboratory, Branch of Shemyakin and Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Pushchino, Russia.
Front Pharmacol. 2023 Feb 22;14:1091858. doi: 10.3389/fphar.2023.1091858. eCollection 2023.
Pharmacokinetic characteristics as well as cognitive-enhancing nootropic activity of latrepirdine (Dimebon) in relationship with its polymorphic forms have been studied in SD and Wistar rats. The pharmacokinetics of six polymorphs (A, B, C, D, E, F) of latrepirdine were studied in male SD rats after 7 days of oral administration in corn oil at a dose of 10 mg/kg once a day. Blood and brain samples were taken on the 7th day of administration at 15 min, 30 min, 60 min and 120 min after administration and analyzed for latrepirdine content by LC-MS. The cognitive-enhancing nootropic effect was studied in male and female Wistar rats after 9 days of oral administration in corn oil at a dose of 10 mg/kg, after prior administration of scopolamine, an agent that causes memory impairment similar to that in Alzheimer's disease. The animals' cognitive function was studied in the passive avoidance test. When studying the pharmacokinetics, the highest bioavailability both in the blood and in the brain was demonstrated by polymorph E, whose AUC was the highest relative to other polymorphs. In the study of the cognitive-enhancing nootropic effect, polymorph E also showed the highest activity, whose values of the latent period of entering the dark chamber did not differ from control animals, and differed from other polymorphs. Thus, the crystal structure has been shown to play a key role in the bioavailability and efficacy of latrepirdine, and polymorph E has also been shown to be a promising drug for the treatment of neurodegenerative diseases associated with memory impairment, such as Alzheimer's disease.
已在SD大鼠和Wistar大鼠中研究了latrepirdine（Dimebon）的药代动力学特征及其与多晶型形式相关的认知增强益智活性。在雄性SD大鼠中，以10mg/kg的剂量每天一次在玉米油中口服给药7天后，研究了latrepirdine六种多晶型物（A、B、C、D、E、F）的药代动力学。在给药第7天，于给药后15分钟、30分钟、60分钟和120分钟采集血液和脑样本，并通过LC-MS分析latrepirdine含量。在雄性和雌性Wistar大鼠中，在以10mg/kg的剂量在玉米油中口服给药9天后，先给予东莨菪碱（一种可引起类似于阿尔茨海默病的记忆损害的药物），然后研究其认知增强益智作用。通过被动回避试验研究动物的认知功能。在研究药代动力学时，多晶型物E在血液和脑中均表现出最高的生物利用度，其AUC相对于其他多晶型物最高。在认知增强益智作用的研究中，多晶型物E也表现出最高的活性，其进入暗室的潜伏期值与对照动物无差异，且与其他多晶型物不同。因此，晶体结构已被证明在latrepirdine的生物利用度和疗效中起关键作用，并且多晶型物E也已被证明是治疗与记忆损害相关的神经退行性疾病（如阿尔茨海默病）的有前景的药物。
