Federal State Budgetary Institution "N.N. Blokhin National Medical Research Center of Oncology" of the Ministry of Health of the Russian Federation, Kashirskoe sh. 24, 115478, Moscow, Russian Federation.
Eur J Drug Metab Pharmacokinet. 2024 Jan;49(1):57-69. doi: 10.1007/s13318-023-00871-3. Epub 2023 Dec 1.
Cyclophilin A (CypA) is an isomerase that functions as a chaperone, housekeeping protein, and cyclosporine A (CsA) ligand. Secreted CypA is a proinflammatory factor, chemoattractant, immune regulator, and factor of antitumor immunity. Experimental data suggest clinical applications of recombinant human CypA (rhCypA) as a biotherapeutic for cancer immunotherapy, stimulation of tissue regeneration, treatment of brain pathologies, and as a supportive treatment for CsA-based therapies. The objective of this study is to analyze the pharmacokinetics of rhCypA in a mouse model.
rhCypA was isotope-labeled with I and injected intraperitoneally (i.p.) or subcutaneously (s/c) into female mice as a single dose of 100 μg per mouse, equivalent to the estimated first-in-human dose. Analysis of I-rhCypA biodistribution and excretion was performed by direct radiometry of the blood, viscera, and urine of mice 0.5-72 h following its administration.
rhCypA showed rapid and even tissue-organ distribution, with the highest tropism (f = 1.56) and accumulation (maximum concentration, C = 137-167 μg/g) in the kidneys, its primary excretory organ. rhCypA showed the lowest tropism to the bone marrow and the brain (f = 0.07) but the longest retention in these organs [mean retention time (MRT) = 25-28 h].
This study identified promising target organs for rhCypA's potential therapeutic effects. The mode of rhCypA accumulation and retention in organs could be primarily due to the expression of its receptors in them. For the first time, rhCypA was shown to cross the blood-brain barrier and accumulate in the brain. These rhCypA pharmacokinetic data could be extrapolated to humans as preliminary data for possible clinical trials.
亲环素 A（CypA）是一种具有分子伴侣、管家蛋白和环孢素 A（CsA）配体功能的异构酶。分泌型 CypA 是一种促炎因子、趋化因子、免疫调节剂和抗肿瘤免疫因子。实验数据表明，重组人 CypA（rhCypA）可作为癌症免疫治疗、组织再生刺激、脑病理学治疗以及作为 CsA 为基础的治疗的辅助治疗的生物治疗剂进行临床应用。本研究的目的是分析 rhCypA 在小鼠模型中的药代动力学。
rhCypA 用 I 进行同位素标记，并以 100μg/只小鼠（相当于估计的首次人体剂量）的剂量经腹腔内（i.p.）或皮下（s/c）注射到雌性小鼠体内。给药后 0.5-72 小时，通过直接放射测量小鼠的血液、内脏和尿液中 I-rhCypA 的生物分布和排泄情况。
rhCypA 显示出快速且均匀的组织器官分布，对肾脏（其主要排泄器官）的亲和力最高（f=1.56），积累量最大（最大浓度，C=137-167μg/g）。rhCypA 对骨髓和大脑的亲和力最低（f=0.07），但在这些器官中的保留时间最长（平均保留时间，MRT=25-28 小时）。
本研究确定了 rhCypA 潜在治疗效果的有希望的靶器官。rhCypA 在器官中的积累和保留模式可能主要归因于其在这些器官中的受体表达。首次表明 rhCypA 可穿过血脑屏障并在大脑中积累。这些 rhCypA 药代动力学数据可外推至人类，作为可能临床试验的初步数据。
