Optimization of experimental settings of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), like the contrast administration protocol, is of great importance for reliable quantification of the microcirculatory properties, such as the volume transfer-constant Ktrans. Using system identification theory and computer simulations, the confounding effects of volume, rate and multiplicity of a contrast injection on the reliability of Ktrans estimation was assessed. A new tracer-distribution model (TDM), based on in vivo data from rectal cancer patients, served to describe the relation between the contrast agent injection and the blood time-course. A pharmacokinetic model (PKM) was used to describe the relation between the blood and tumor tissue time-courses. By means of TDM and PKM in series, the tissue-transfer function of the PKM was analyzed. As both the TDM and PKM represented low-frequency-pass filters, the energy-density at low frequencies of the blood and tissue time-courses was larger than at high frequencies. The simulations, based on measurements in humans, predict that the Ktrans is most reliable with a high injection volume administered in a single injection, were high rates only modestly improve Ktrans.