Role of nucleoside transport inhibition and endogenous adenosine in prevention of catecholamine induced death in rabbits

Belle, H. Van; Donck, Kris Ver; Verheyen, Willy

doi:10.1093/cvr/27.1.111

Cited by 11 publications

(4 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Draflazine (Figure 1 ) is a nucleoside transport inhibitor showing cardioprotective effects in various in uitro experiments and animal models [16][17][18][19][20][21][22][23][24]. Moreover, draflazine shows high potency on a molar basis in inhibiting the breakdown of adenosine by washed human erythrocytes [ 16, 171. The aim of the present study in healthy male subjects was to investigate the pharmacokinetics of draflazine and their relationship to the measured adenosine breakdown inhibition e x ciz'o after a single i.v.…”

Section: Introduction Methodsmentioning

confidence: 99%

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

Snoeck¹,

Jacqmin²,

Peer³

et al. 1996

Br J Clin Pharmacol

View full text Add to dashboard Cite

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 uiuo, which served as a pharmacodynamic endpoint. 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 , was 0.87 ng ml-1 plasma and the maximal specific binding capacity (Bmax) was 164ngml-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. The pharmacokinetics of draflazine in blood were determined in each subject and characterized by a two-compartment pharmacokinetic model. The pharmacokinetic parameters (mean f s.d.) were: clearance 22.0 f 8.0 ml rnin-', volume of distribution at steady-state 39.8 & 4.7 1 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-', volume of distribution at steady-state 349 1 and terminal half-life 10.7 h. A non-linear relationship was observed between the plasma or blood concentration of draflazine and the ABI determined ex uivo. This relationship was characterized by the sigmoidal Emax pharmacodynamic model. Based on concentrations in pooled plasma, values of the pharmacodynamic parameters were Emax loo%, 10.5 ng ml-I and Hill factor 0.9. When using whole blood concentrations, the relationship was much steeper with values (mean & s.d.) Emax 92.4 & 5.6%, IC,o 76.0 & 15.3 ng ml-' and Hill factor 3.5 f 0.9. 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. Keywords draflazine nucleoside transport inhibitor non-linear red blood cell partitioning pharmacokinetics pharmacodynamics adenosine breakdown inhibition red blood cell occupancy

show abstract

Section: Introduction Methodsmentioning

confidence: 99%

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

Snoeck¹,

Jacqmin²,

Peer³

et al. 1996

Br J Clin Pharmacol

View full text Add to dashboard Cite

show abstract

“…Aminophylline also reduced the survival of controls (endogenous adenosine!). Thus R 75 231 could still protect against death in the presence of aminophylline when compared to aminophylline-treated controls [72]. Reduction of infarct size in dogs has been reported for dipyridamole [73], dilazep [74], mioflazine [75 76], and lidoflazine [77].…”

Section: In Vivo Modelsmentioning

confidence: 92%

Purine metabolism in the heart

Donck

1994

Pharm World Sci

View full text Add to dashboard Cite

Adenosine has recently received much attention for the protection it provides against the deleterious effects of ischaemia reperfusion. Whenever the demand for oxygen exceeds its supply, adenosine triphosphate in myocytes is rapidly dephosphorylated to adenosine. Adenosine may then protect the myocardium against ischaemia-reperfusion damage. However, the accumulation of adenosine is limited by its rapid uptake and catabolism in the endothelium and in red blood cells. The strict compartmentalization of the enzyme pathways involved in the metabolism of adenosine, e.g. adenosine production by myocytes, its pharmacological action in the interstitium, its catabolism in the endothelium and in red blood cells, and its carrier-mediated transport across membranes, provides a unique target for pharmacological interventions. Blockade of adenosine uptake may indeed result in prolonged adenosine accumulation specifically in those regions of the heart where it is produced. In recent years considerable evidence has been gathered on the adenosine-mediated cardioprotective actions of nucleoside transport inhibitors.

show abstract

“…Draflazine ( Figure 1 ) is a nucleoside transport inhibitor showing cardioprotective effects in various in uitro experiments and animal models [16][17][18][19][20][21][22][23][24]. Moreover, draflazine shows high potency on a molar basis in inhibiting the breakdown of adenosine by washed human erythrocytes [ 16, 171. The aim of the present study in healthy male subjects was to investigate the pharmacokinetics of draflazine and their relationship to the measured adenosine breakdown inhibition e x ciz'o after a single i.v.…”

Section: Introduction Methodsmentioning

confidence: 99%

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

Snoeck

Jacqmin

Peer

et al. 1996

Brit J Clinical Pharma

View full text Add to dashboard Cite

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 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 Emax pharmacodynamic model. Based on concentrations in pooled plasma, values of the pharmacodynamic parameters were Emax 100%, IC50 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.) Emax 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 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.

show abstract

Role of nucleoside transport inhibition and endogenous adenosine in prevention of catecholamine induced death in rabbits

Cited by 11 publications

References 0 publications

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

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

Purine metabolism in the heart

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

Contact Info

Product

Resources

About