The implications of non-linear red blood cell partitioning for the pharmacokinetics and pharmacodynamics of the nucleoside transport inhibitor draflazine

British Journal of Clinical Pharmacology
E SnoeckJ Heykants

Abstract

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/plasma distribution of draflazine was non-linear and characterized as a capacity-limited specific binding to the nucleoside transporter on the red blood cells. The binding (dissociation) constant Kd was 0.87 ng ml-1 plasma and the maximal specific binding capacity (Bmax) was 164 ng ml-1 RBC, which corresponds to about 14,000 specific binding sites 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 pharmacokinetic model. The pharmacokinetic parameters (mean +/- s.d.) were: clearance 22.0 +/- 8.0 ml mm-1, volume of distribution at steady-state 39.8 +/- 4.7 l 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 binding assay....Continue Reading

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