Ion-selective electrodes (ISEs) containing neutral ionophores are used in clinical, industrial, and environmental analysis. The wide range of applications requires deep theoretical description. This work concentrates on the development of the general approach to the description of electro-diffusion processes, namely, Nernst-Planck-Poisson (NPP) model to allow the description of the time-dependent responses in the case of complexation reactions occurring in the ion-selective membranes. The impact of the chemical reaction on the calibration curves and apparent selectivity of ISE is discussed. Results obtained using NPP model with time-dependent reaction are compared with those obtained with the Phase Boundary Model (PBM), as well as with the previous solutions of NPP model, using the infinite reaction rates and constant ligand concentration assumption. The validity of these assumptions is investigated and the limitations of PBM in the description of neutral-carrier ISE are discussed.