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 intracellular deamination into inactive inosine (INO) and further breakdown into hypoxanthine (HYPO). The model and its parameters were based on previous studies investigating the kinetics of the biochemical mechanism of uptake and metabolism of ADO in human erythrocytes. Application of the model for simulations of the breakdown of ADO in a RBC suspension 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 measured ABI and the nucleoside transporter occupancy of draflazine. Intracellular deamination of ADO rather than its transport by the nucleoside transporter is the rate-limiting step in the overall catabolism of ADO. Consequently, at least 90% occupancy of the transporter by draflazine 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 clinical 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 manner after a continuous infusion of draflazine. Finally, the previously found different sigmoidal Emax relationships between the measured ABI and the concentrations of draflazine in plasma and whole blood could be explained by the ADO transport and breakdown RBC kinetic model and the capacity-limited specific RBC binding characteristics of draflazine.
Snoeck
E
E
Department of Clinical Pharmacokinetics, Janssen Research Foundation, Beerse, Belgium.
Ver Donck
K
K
Jacqmin
P
P
Van Belle
H
H
Dupont
A G
AG
Van Peer
A
A
Danhof
M
M
D000241:Adenosine / Q000378:metabolism*; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004912:Erythrocytes / Q000378:metabolism*; D006801:Humans; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008954:Models, Biological; D033703:Nucleoside Transport Proteins; D010879:Piperazines / Q000378:metabolism*
D002352:Carrier Proteins; D008565:Membrane Proteins; D033703:Nucleoside Transport Proteins; D010879:Piperazines; C072040:draflazine; D000241:Adenosine