THE IMPLICATIONS OF NONLINEAR RED-BLOOD-CELL PARTITIONING FOR THE PHARMACOKINETICS AND PHARMACODYNAMICS OF THE NUCLEOSIDE TRANSPORT INHIBITOR DRAFLAZINE

1 Draflazine, a nucleoside transport inhibitor, was administered as a 15 min i.v. infusion of 2.5 mg to eight healthy male subjects. Plasma and whole blood concentrations were measured up to 32 h post-dose, and were related to adenosine breakdown inhibition (ABI) measured ex vivo , which served as a pharmacodynamic endpoint. 2 The red blood cell/pla sma distribution of draflazine was non-linear and characterized as a c apacity-limited specific binding to the nucleoside transporter on the red blood cells. The binding (dissociation) constant K-d was 0.87 ng m l(-1) plasma and the maximal specific binding capacity (B-max) was 164 ng ml(-1) RBC, which corresponds to about 14 000 specific binding sit es per erythrocyte. Non-specific binding amounted to less than 15% of the total, binding. 3 The pharmacokinetics of draflazine in blood were determined in each subject and characterized by a two-compartment pha rmacokinetic model. The pharmacokinetic The pharmacokinetic parameters (mean +/- s.d.) were: clearance 22.0 +/- 8.0 ml min(-1), volume of di stribution at steady-state 39.8 +/- 4.71 and terminal half-life 24.0 /- 9.4 h. Concentrations in plasma were much lower, and could only be determined accurately in pooled plasma samples with a red blood cell b inding assay. The pharmacokinetic parameters in pooled plasma were: cl earance 551 ml min(-1), volume of distribution at steady-state 349 1 a nd terminal half-life 10.7 h. 4 A non-linear relationship was observed between the plasma or blood concentration of draflazine and the ABI d etermined ex vivo. This relationship was characterized by the sigmoida l E(max) pharmacodynamic model. Based on concentrations in pooled plas ma, values of the pharmacodynamic parameters were E(max) 100%, IC50 10 .5 ng ml(-1) and Hill factor 0.9. When using whole blood concentration s: the relationship was much steeper with values (mean +/- s.d.) E(max ) 92.4 +/- 5.6%, IC50 76.0 +/- 15.3 ng ml(-1) and Hill factor 3.5 +/- 0.9. 5 Binding to the nucleoside transporter on red blood cells is an important determinant of the pharmacokinetics of draflazine and a high degree of occupancy of the transporter by draflazine is required to i nhibit adenosine breakdown ex vivo. It is suggested that red blood cel l nucleoside transporter occupancy may serve as a useful pharmacodynam ic endpoint in dose ranging studies with draflazine.