Superior Therapeutic Index of Calmangafodipir in Comparison to Mangafodipir

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 disso-ciation of Mn2+ from mangafodipir—about 80 % dissociates after injection. The SOD mimetic activity, however, de-pends on the intact Mn complex. Complexed Mn2+ is readily excreted in the urine, whereas dissociated Mn2+ 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 Mn2+ in mangafodipir with Ca2+ (resulting in calmangafodipir) stabilizes it from releasing Mn2+ after administration, which roughly doubles renal excretion of Mn. A considerable part of Mn2+ release frommangafodipir is governed by the presence of a limited amount of plasma zinc (Zn2+). Zn2+ has roughly 103 and 109 times highe