PHYSIOLOGICAL RED-BLOOD-CELL KINETIC-MODEL TO EXPLAIN THE APPARENT DISCREPANCY BETWEEN ADENOSINE BREAKDOWN INHIBITION AND NUCLEOSIDE TRANSPORTER OCCUPANCY OF DRAFLAZINE

A physiological red blood cell (RBC) kinetic model is proposed for the adenosine (ADO) transport into erythrocytes and its subsequent intrac ellular deamination into inactive inosine (INO) and further breakdown into hypoxanthine (HYPO). The model and its parameters were based on p revious studies investigating the kinetics of the biochemical mechanis m of uptake and metabolism of ADO in human erythrocytes. Application o f the model for simulations of the breakdown of ADO in a RBC suspensio n revealed that the predicted adenosine breakdown inhibition (ABI) of draflazine corresponded well with the ABI measured ex vivo. The model definitely explained the apparent discrepancy between the ex vivo meas ured ABI and the nucleoside transporter occupancy of draflazine. Intra cellular deamination of ADO rather than its transport by the nucleosid e transporter is the rate-limiting step in the overall catabolism of A DO. Consequently, at least 90% occupancy of the transporter by draflaz ine is required to inhibit adenosine breakdown ex vivo substantially. Simulations on basis of the validated model were performed to evaluate the ABI for different experimental conditions and to mimic the clinic al situation, The latter may be very helpful for the design of optimal dosing schemes of draflazine. It was demonstrated that the short half -life of released ADO was prolonged substantially in a dose-related ma nner after a continuous infusion of draflazine. Finally, the previousl y found different sigmoidal E-max relationships between the measured A BI and the concentrations of draflazine in plasma and whole blood coul d be explained by the ADO transport and breakdown RBC kinetic model an d the capacity-limited specific RBC binding characteristics of draflaz ine.