Comparison of the Existing Nucleoside Transport Inhibitors: in vitro and in vivo Data

Abstract

In order to exclude intracellular metabolism and its interference with the transport process, most studies on nucleoside transport and nucleoside transport inhibition apply either ligand binding and displacement, or rapid kinetic procedures of a few seconds (the present day programme is just another illustration). Although in these ways interesting information can be, and has been, gathered for the characterization of the transporter, the situation is far from what may happen in vivo. For instance, during myocardial ischemia, local concentrations of adenosine (ADO) may become very high (10⁻⁵-10⁻⁴ M), and remain so for extended periods of time (many minutes). The role of the transporter in the endothelial cells is the removal of ADO from its site of production by carrying it into those cells where it is rapidly catabolized. The concerted action of transporter and metabolism is an absolute requirement. Applying, under these conditions, an adenosine deaminase inhibitor may leave the transporter intact but ADO will not be removed. Upon reperfusion, the transporter will facilitate the passage of ADO through the otherwise tight endothelial layer, so that it is rapidly lost by dilution into the circulation. If the ischemic area is limited, so that the circulating concentration of ADO is not substantially increased, inhibition of adenosine deaminase will hardly affect the rate of removal during reperfusion. Keeping that in mind, I believe that, since our goal is to prolong the concentration of local ADO whenever and wherever it is produced, our approach of looking at the effect of nucleoside transport inhibitors on the rate of disappearance of ADO in a cell suspension can be justified-provided of course that these drugs have no effect on the metabolic steps.