Abstract
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 measuredex 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 vivosubstantially. 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 sigmoidalEmax 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.
Footnotes
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Send reprint requests to: Eric Snoeck, PhD, International Clinical Research and Development, Department of Clinical Pharmacokinetics, Janssen Research Foundation, Turnhoutseweg 30, B-2340 Beerse, Belgium.
- Abbreviations:
- ABI
- adenosine breakdown inhibition
- ADA
- adenosine deaminase
- ADO
- adenosine
- CABG
- coronary artery bypass grafting
- Emax
- maximal effect (maximal ABI)
- HPLC
- high-performance liquid chromatography
- HYPO
- hypoxanthine
- IC50
- concentration that produces 50% of the maximal ABI
- INO
- inosine
- PK-PD
- pharmacokinetic-pharmacodynamics
- PNP
- purine nucleoside phosphorylase
- RBC
- red blood cells
- Received July 7, 1997.
- Accepted March 10, 1998.
- The American Society for Pharmacology and Experimental Therapeutics
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