Comparison of the Existing Nucleoside Transport Inhibitors: in vitro and in vivo Data

Belle, H. Van; Wynants, J.; Donck, Kris Ver

doi:10.1007/978-1-4899-2638-8_96

Cited by 8 publications

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“…For this reason, the Kd measured in the absence of plasma proteins will be much lower. This was demonstrated previously by Van Belle et al [17], as the in vitro IC,, for the inhibition of the breakdown of adenosine in undiluted human plasma was 5-to 6-fold higher than the IC,, in washed human red blood cells.…”

Section: Resultssupporting

confidence: 72%

“…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%

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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

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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.

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Section: Resultssupporting

confidence: 72%

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

Self Cite

View full text Add to dashboard Cite

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

Snoeck¹,

Jacqmin²,

Peer³

et al. 1996

Br J Clin Pharmacol

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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

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“…A 2a AR, A 2b AR, and A 3 AR have also been implicated in the recently discovered phenomenon of postconditioning (22,59). NT inhibition not only causes extracellular accumulation of adenosine, but it can also cause retention/trapping of adenosine within cardiomyocytes (1,54), which can help replenish essential adenine nucleotides, such as ATP. Specificity of NBMPR and congeners is known to be different from that of other NT inhibitors such as the lidoflazine analogs or dipyridamole (14).…”

Section: Discussionmentioning

confidence: 99%

Cardioprotective effects of novel tetrahydroisoquinoline analogs of nitrobenzylmercaptopurine riboside in an isolated perfused rat heart model of acute myocardial infarction

Zhu¹,

Hofmann²,

Buolamwini³

2007

American Journal of Physiology-Heart and Circulatory Physiology

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We have investigated the cardioprotective effects of novel tetrahydroisoquinoline nitrobenzylmercaptopurine riboside (NBMPR) analog nucleoside transport (NT) inhibitors, compounds 2 and 4, in isolated perfused rat hearts. Langendorff-perfused heart preparations were subjected to 10 min of treatment with compound 2, compound 4, or vehicle (control) followed by 30 min of global ischemia and 120 min of reperfusion. For determination of infarct size, reperfusion time was 180 min. At 1 microM, compounds 2 and 4 provided excellent cardioprotection, with left ventricular developed pressure (LVDP) recovery and end-diastolic pressure (EDP) increase of 82.9 +/- 4.0% (P<0.001) and 14.1 +/- 2.0 mmHg (P<0.03) for compound 2-treated hearts and 79.2 +/- 5.9% (P<0.002) and 7.5 +/- 2.7 mmHg (P<0.01) for compound 4-treated hearts compared with 41.6 +/- 5.2% and 42.5 +/- 6.5 mmHg for control hearts. LVDP recovery and EDP increase were 64.1 +/- 4.2% and 29.1 +/- 2.5 mmHg for hearts treated with 1 microM NBMPR. Compound 4 was the best cardioprotective agent, affording significant cardioprotection, even at 0.1 microM, with LVDP recovery and EDP increase of 76.0 +/- 4.9% (P<0.003) and 14.1 +/- 1.0 mmHg (P<0.03). At 1 microM, compound 4 and NBMPR reduced infarct size, with infarct area-to-total risk area ratios of 29.13 +/- 3.17 (P<0.001) for compound 4 and 37.5 +/- 3.42 (P<0.01) for NBMPR vs. 51.08 +/- 5.06% for control hearts. Infarct size was more effectively reduced by compound 4 than by NBMPR (P<0.02). These new tetrahydroisoquinoline NBMPR analogs are not only potent cardioprotective agents but are, also, more effective than NBMPR in this model.

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Comparison of the Existing Nucleoside Transport Inhibitors: in vitro and in vivo Data

Cited by 8 publications

References 1 publication

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

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

Cardioprotective effects of novel tetrahydroisoquinoline analogs of nitrobenzylmercaptopurine riboside in an isolated perfused rat heart model of acute myocardial infarction

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