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PURPOSE: To assess which MRI-derived kinetic parameters reflect decreased transvascular and interstitial transport when low- and high-molecular-weight agents are used in rat hepatocellular carcinomas. MATERIALS AND METHODS: Dynamic MRI after injection of a low-molecular-weight contrast agent of 0.56 kDa (Gd-DOTA, gadoterate) and two high-molecular-weight contrast agents of 6.47 kDa (P792, gadomelitol) and 52 kDa (P717, carboxymethyldextran Gd-DOTA) was performed in rats with chemically induced hepatocellular carcinomas. The data were analyzed with the Kety compartmental model, the extended Kety compartmental model in which it is assumed that the tissue voxels contain a vascular component, and the St Lawrence and Lee distributed-parameter model. RESULTS: The extravascular extracellular space accessible to the contrast agent v(e) and the extraction fraction E decreased with increasing molecular weight of the contrast agent. In contrast, the volume transfer constant Ktrans did not differ significantly when low- or high-molecular-weight agents were used. CONCLUSION: In this animal model the results suggest that the accessible extravascular extracellular space and the extraction fraction are more sensitive indicators of decreased transvascular and interstitial transport with high-molecular-weight agents than the volume transfer constant, which is a lumped representation of blood flow and permeability. J. Magn. Reson. Imaging 2008;28:906-914. (c) 2008 Wiley-Liss, Inc.