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The implications of non‐linear red blood cell partitioning for the pharmacokinetics and pharmacodynamics of the nucleoside transport inhibitor draflazine
Author(s) -
SNOECK E.,
JACQMIN P.,
PEER A.,
DANHOF M.,
DONCK K.,
BELLE H.,
WOESTENBORGHS R.,
CRABBÉ R.,
GOOL R.,
DUPONT A.,
HEYKANTS J.
Publication year - 1996
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1111/j.1365-2125.1996.tb00116.x
Subject(s) - pharmacokinetics , pharmacodynamics , pharmacology , nucleoside , medicine , chemistry , biochemistry
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 K d was 0.87 ng ml ‐1 plasma and the maximal specific binding capacity (B max ) was 164ng ml ‐1 RBC, which corresponds to about 14000 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 pharm‐acokinetic parameters (mean ± s.d.) were: clearance 22.0 ± 8.0 ml min ‐1 , volume of distribution 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 binding assay. The pharmacokinetic parameters in pooled plasma were: clearance 551 ml min ‐1 , volume of distribution at steady‐state 3491 and terminal half‐life 10.7 h. 4 A non‐linear relationship was observed between the plasma or blood concentration of draflazine and the ABI determined ex vivo. This relationship was characterized by the sigmoidal E max pharmacodynamic model. Based on concentrations in pooled plasma, values of the pharmacodynamic parameters were E max 100%, I C 50 10.5 ng ml ‐1 and Hill factor 0.9. When using whole blood concentrations, the relationship was much steeper with values (mean ± s.d.) E max 92.4 + 5.6%, I C 50 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 inhibit adenosine breakdown ex vivo. It is suggested that red blood cell nucleoside transporter occupancy may serve as a useful pharmacodynamic endpoint in dose ranging studies with draflazine.