Divison of Drug Research/Pharmacology, Department of Medicine and Health Sciences, Linköping University, Linköping, Sweden ; PledPharma AB, Stockholm, Sweden.
Transl Oncol. 2012 Dec;5(6):492-502. doi: 10.1593/tlo.12238. Epub 2012 Dec 1.
Mangafodipir is a magnetic resonance imaging contrast agent with manganese superoxide dismutase (MnSOD) mimetic activity. The MnSOD mimetic activity protects healthy cells against oxidative stress-induced detrimental effects, e.g., myelosuppressive effects of chemotherapy drugs. The contrast property depends on in vivo dissociation of Mn(2+) from mangafodipir-about 80% dissociates after injection. The SOD mimetic activity, however, depends on the intact Mn complex. Complexed Mn(2+) is readily excreted in the urine, whereas dissociated Mn(2+) is excreted slowly via the biliary route. Mn is an essential but also a potentially neurotoxic metal. For more frequent therapeutic use, neurotoxicity due to Mn accumulation in the brain may represent a serious problem. Replacement of 4/5 of Mn(2+) in mangafodipir with Ca(2+) (resulting in calmangafodipir) stabilizes it from releasing Mn(2+) after administration, which roughly doubles renal excretion of Mn. A considerable part of Mn(2+) release from mangafodipir is governed by the presence of a limited amount of plasma zinc (Zn(2+)). Zn(2+) has roughly 10(3) and 10(9) times higher affinity than Mn(2+) and Ca(2+), respectively, for fodipir. Replacement of 80% of Mn(2+) with Ca(2+) is enough for binding a considerable amount of the readily available plasma Zn(2+), resulting in considerably less Mn(2+) release and retention in the brain and other organs. At equivalent Mn(2+) doses, calmangafodipir was significantly more efficacious than mangafodipir to protect BALB/c mice against myelosuppressive effects of the chemotherapy drug oxaliplatin. Calmangafodipir did not interfere negatively with the antitumor activity of oxaliplatin in CT26 tumor-bearing syngenic BALB/c mice, contrary calmangafodipir increased the antitumor activity.
镁钆弗塞匹尔是一种具有锰超氧化物歧化酶（MnSOD）模拟活性的磁共振成像对比剂。这种 MnSOD 模拟活性可以保护健康细胞免受氧化应激诱导的有害影响，例如化疗药物的骨髓抑制作用。其对比特性取决于体内 Mn(2+)与镁钆弗塞匹尔的解离——注射后约有 80%解离。然而，SOD 模拟活性取决于完整的 Mn 络合物。络合的 Mn(2+)很容易通过尿液排泄，而解离的 Mn(2+)则通过胆汁途径缓慢排泄。Mn 是一种必需但也潜在神经毒性的金属。为了更频繁地治疗用途，由于 Mn 在大脑中的积累而导致的神经毒性可能是一个严重的问题。用 Ca(2+)（生成钙镁钆弗塞匹尔）替代镁钆弗塞匹尔中 4/5 的 Mn(2+)（从而稳定其在给药后释放 Mn(2+)），可使 Mn 的肾脏排泄量大致增加一倍。镁钆弗塞匹尔中 Mn(2+)的释放很大程度上受血浆中有限量锌（Zn(2+)）的存在所控制。Zn(2+)与 Mn(2+)和 Ca(2+)的亲和力分别大约高 10(3)和 10(9)倍， fodipir 分别是 Mn(2+)和 Ca(2+)的 10(3)和 10(9)倍。用 Ca(2+)替代 80%的 Mn(2+)足以结合相当数量的现成血浆 Zn(2+)，从而导致 Mn(2+)在大脑和其他器官中的释放和保留明显减少。在等效的 Mn(2+)剂量下，钙镁钆弗塞匹尔对 BALB/c 小鼠奥沙利铂化疗药物的骨髓抑制作用的保护作用明显优于镁钆弗塞匹尔。钙镁钆弗塞匹尔不会对 CT26 荷瘤同基因 BALB/c 小鼠中奥沙利铂的抗肿瘤活性产生负面影响，反而会增强其抗肿瘤活性。
