Biodistribution and toxicity of MR imaging contrast media

Abstract

ISIGNAL INTENSITY on a magnetic resonance (MR) image is mainly determined by proton density and T1 and T2. Image contrast, described as the difference in signal intensity between two tissues, is dependent on a number of physical parameters and can be altered by changing these parameters. Contrast agents are pharmaceuticals that can accentuate the difference in signal intensity between two adjacent tissue compartments by directly interfering with the proton relaxation times in one more than in the other. Such agents are designed with the purpose of improving image contrast between normal and abnormal tissues and may enhance the contrast positively or negatively, depending on their relative T1, T2, or T2* effects. Effec tive MR imaging contrast agents include paramagnetic (metal ions such as gadolinium, manganese, dysprosium, iron; free radicals: nitrous oxides), magnetic (superparamagnetic or ferromagnetic iron oxide particles), or diamagnetic (substances that displace hydrogen nuclei such as gases, deuterated water, perfluorocarbons) materials.The clinical effect of an MR imaging contrast medium is determined not only by the contrast-enhancing properties of the compound but also by its pharmacokinetic properties, which determine where the agent is distributed in the body and the length of time adequate concentrations are maintained in target organs. Furthermore, it is of crucial importance that the drug be well tolerated when given in doses necessary to achieve the clinical effect. Before a new chemical entity is introduced into humans as a drug, it is extensively studied in animals with respect to properties mentioned above. When the re1axivit.y effect of a contrast agent can be measured in vitro, the most important factors to study preclinically in animal experimental models are tolerance, distribution, and elimination in relevant species. The tolerance is riormally assessed during acute and subacute toxicity studies, in addition to more specific safety studies in critical organ systems such as cardiovascular, hepatobiliary, and renal systems. The safety profile is further extended through studies that examine effects on overall reproduction and on specific genetic modifications (mutagenicity), while ADME (absorbtion, distribution, metabolism, excretion) studies are performed to investigate pharmacokinetic properties. In this article, the main principles of the pharmacokinetic and toxicologic properties of the most important classes of contrast media are discussed. We focus on groups of contrast media in clinical use or under investigation; future developments such as immuno-and disease-specific concepts are not included. AGENTS DISTRIBUTED IN THE EXTRACELLULAR FLUID (ECF)Gadolinium: General Aspects the largest number of unpaired electrons and is thus, theoretically, the most efficient T1 relaxation metal that can be used in contrast media for MR imaging. However, when administered as the free gadolinium ion, the metal is not suitable as a contrast medium for three reasons: ( a ) its toxicity, ( b ) its pharmac...

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