Drug-eluting stent (DES) is a common approach to mitigate restenosis, a major drawback of stent-based treatment in coronary disease. However, the long-term effect of this mode of treatment is unknown. A detailed study of the drug delivery system is expected to give a better insight about what is required to improve the design of DES to achieve its long-term therapeutic effect. Physiological transport forces, drug physiochemical properties and drug interaction with the vascular tissue are the main factors which govern the local pharmacokinetics of DES. We hypothesized that these factors should be coupled in modeling drug delivery. In this study, a 2-dimensional model which drug transfer was coupled with both luminal and transmural flow and drug binding was used to investigate the drug release, deposition and distribution in the arterial wall. Two model drugs, paclitaxel (hydrophobic) and heparin (hydrophilic), were used to examine how the nature of the drug affects the pharmacokinetics. Moreover, drug interaction with the binding sites was treated as a reversible binding process which is a function of free and bound drug concentration in the arterial wall. Our results show that, for hydrophobic drug, the effect of coupling drug transfer with both luminal and transmural flow and drug binding is significant. On the other hand, for hydrophilic drug, transmural flow shows negligible effect on drug delivery. Incorporation of drug binding in the model increases markedly the retention time of drug in the arterial wall. It is therefore important to consider the coupling factors in modeling the local pharmacokinetics of DES. This study provides further insights which have not been offered in reported models based on either luminal or transmural flow, with or without drug binding.