POPULATION ANALYSIS OF THE NON-LINEAR RED-BLOOD-CELL PARTITIONING ANDTHE CONCENTRATION-EFFECT RELATIONSHIP OF DRAFLAZINE FOLLOWING VARIOUSINFUSION RATES

Aims To investigate the impact of the specific red blood cell binding on the pharmacokinetics and pharmacodynamics of the nucleoside transpo rt inhibitor draflazine after i.v. administration at various infusion rates. It was also aimed to relate the red blood cell (RBC) occupancy of draflazine to the ex vivo measured adenosine breakdown inhibition ( ABI). Methods Draflazine was administered to healthy volunteers as a 1 5-min i.v. infusion of 0.25, 0.5, 1, 1.5 and 2.5 mg immediately follow ed by an infusion of the same dose over 1 h. Plasma and whole blood co ncentrations were measured up to 120 h post dose, and were related to the ex vivo measured ABI, serving as a pharmacodynamic endpoint. The c apacity-limited specific binding of draflazine to the nucleoside trans porter located on the erythrocytes was evaluated by a population appro ach. Results The estimate of the population parameter typical value (% CV) of the binding constant K-d and the maximal specific binding capac ity (B-max) was 0.385 (3.5) ng ml(-1) plasma and 158 (2.1) ng ml(-1) R BC, respectively. The non-specific binding was low. The specific bindi ng to the erythrocytes was a source of non-linearity in the pharmacoki netics of draflazine. The total plasma clearance of draflazine slightl y decreased with increasing doses, whereas the total clearance in whol e blood increased with increasing doses. The sigmoidal E-max equation was used to relate the plasma and whole blood concentration of draflaz ine to the ex vivo determined ABI. In plasma, typical values (%CV) of E-max, IC50 and Hill factor were 81.4 (1.9)%, 3.76 (9.3) ng ml(-1) and 1.06 (3.4), respectively. The relationship in whole blood was much st eeper with population parameter typical values (%CV) of E-max, IC50 an d Hill factor of 88.2 (2.0)%, 65.7 (2.8) ng ml(-1) and 4.47 (5.5), res pectively. The RBC occupancy of draflazine did not coincide with the e x vivo measured ABI. The observed relationship between RBC occupancy a nd ABI was not directly proportional but similar for all studied infus ion schemes. Conclusions The findings of this study show that the occu pancy of the nucleoside transporter by draflazine should be at least 9 0% in order to inhibit substantially adenosine breakdown in vivo. On t he basis of these findings it is suggest 15 min infusion of 1 mg drafl azine followed by an infusion of 1 mg be appropriate in patients under going a coronary artery bypass grafting.