Effect of altered AGP plasma binding on heart rate changes by S(−)‐propranolol in rats using mechanism‐based estimations of in vivo receptor affinity (KB,vivo)

Steeg, Tamara J. van; Krekels, Elke H. J.; Freijer, Jan; Danhof, Meindert; Lange, Elizabeth C. M. de

doi:10.1002/jps.22014

Cited by 8 publications

(4 citation statements)

References 26 publications

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“…The serum level of AGP significantly increases in renal disease patients, and the concomitant reduction in the free concentration of the S -alprenolol, with a large binding constant, was higher than that of the R -isomer, which has a small binding constant 105 . To study the impact of plasma protein binding on pharmacodynamics, Steeg et al 106 indicated that the plasma protein binding of S -propranolol was restricting its effects on heart rate due to the elevated AGP concentration.…”

Section: Stereoselectivity Of Plasma Protein Binding To Chiral Drugsmentioning

confidence: 99%

Stereoselective binding of chiral drugs to plasma proteins

et al. 2013

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Chiral drugs show distinct biochemical and pharmacological behaviors in the human body. The binding of chiral drugs to plasma proteins usually exhibits stereoselectivity, which has a far-reaching influence on their pharmacological activities and pharmacokinetic profiles. In this review, the stereoselective binding of chiral drugs to human serum albumin (HSA), α1-acid glycoprotein (AGP) and lipoprotein, three most important proteins in human plasma, are detailed. Furthermore, the application of AGP variants and recombinant fragments of HSA for studying enantiomer binding properties is also discussed. Apart from the stereoselectivity of enantiomer-protein binding, enantiomer-enantiomer interactions that may induce allosteric effects are also described. Additionally, the techniques and methods used to determine drug-protein binding parameters are briefly reviewed.

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Section: Stereoselectivity Of Plasma Protein Binding To Chiral Drugsmentioning

confidence: 99%

Stereoselective binding of chiral drugs to plasma proteins

et al. 2013

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“…This also means that we have to address heterogeneity of the rates and extents of physiological processes on the causal path between drug administration and CNS effects and have to use study designs in which individual processes can be challenged. This can be done, for example, by changing plasma protein binding [123,124], inhibition of a particular efflux transporter [125], blocking particular receptors [126,127], or by induction of a pathological state [113,128] and enabling us to learn about the contribution of individual processes in CNS target site kinetics [17] and dynamics [129,130]. …”

Section: Resultsmentioning

confidence: 99%

The mastermind approach to CNS drug therapy: translational prediction of human brain distribution, target site kinetics, and therapeutic effects

Lange

2013

Fluids Barriers CNS

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Despite enormous advances in CNS research, CNS disorders remain the world’s leading cause of disability. This accounts for more hospitalizations and prolonged care than almost all other diseases combined, and indicates a high unmet need for good CNS drugs and drug therapies.Following dosing, not only the chemical properties of the drug and blood–brain barrier (BBB) transport, but also many other processes will ultimately determine brain target site kinetics and consequently the CNS effects. The rate and extent of all these processes are regulated dynamically, and thus condition dependent. Therefore, heterogenious conditions such as species, gender, genetic background, tissue, age, diet, disease, drug treatment etc., result in considerable inter-individual and intra-individual variation, often encountered in CNS drug therapy.For effective therapy, drugs should access the CNS “at the right place, at the right time, and at the right concentration”. To improve CNS therapies and drug development, details of inter-species and inter-condition variations are needed to enable target site pharmacokinetics and associated CNS effects to be translated between species and between disease states. Specifically, such studies need to include information about unbound drug concentrations which drive the effects. To date the only technique that can obtain unbound drug concentrations in brain is microdialysis. This (minimally) invasive technique cannot be readily applied to humans, and we need to rely on translational approaches to predict human brain distribution, target site kinetics, and therapeutic effects of CNS drugs.In this review the term “Mastermind approach” is introduced, for strategic and systematic CNS drug research using advanced preclinical experimental designs and mathematical modeling. In this way, knowledge can be obtained about the contributions and variability of individual processes on the causal path between drug dosing and CNS effect in animals that can be translated to the human situation. On the basis of a few advanced preclinical microdialysis based investigations it will be shown that the “Mastermind approach” has a high potential for the prediction of human CNS drug effects.

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“…Alpha-1-acid glycoprotein level was significantly higher at 2 days post surgery when compared with 7 days post surgery affecting the estimation of S-propranolol in vivo affinity. In other words, a tenfold increase in serum alpha-1-acid glycoprotein concentration changed the estimate for in vivo receptor affinity of S-propranolol on the basis of total plasma concentrations from 7.0 to 30 nM [56]. These results suggest that plasma protein binding restricts the PDs of S(-)-propranolol and unbound plasma concentrations of the β-blocker need to be considered for accurate PD estimation [56].…”

Section: Preclinical Pk/pd Studies With β-Blockersmentioning

confidence: 99%

PK/PD Modeling of β-Blockers in Cardiovascular Disease: An Update

Höcht

Bertera

Mauro

et al. 2016

Int. J. Pharmacokinet.

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Review β-blockers play a central role in the treatment of the various main cardiovascular diseases, including hypertension, coronary artery disease and systolic heart failure. As a therapeutic class, β-blockers form a heterogeneous family that differs in their pharmacokinetic (PK) and pharmacodynamic (PD) properties, highlighting the relevance of the extensive evaluation of PK/PD properties of these agents in order to optimize the outcomes of the treatment of cardiovascular diseases. Preclinical and clinical studies using PK/PD models have been able to identify different factors associated with cardiovascular response of β-blockers, including age, pharmaceutical formulation and genetic polymorphism, among others. PK/PD modeling of β-blockers can also be attractive for the early detection of poor responders and the optimization of dose regimen in their different indications.

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Effect of altered AGP plasma binding on heart rate changes by S(−)‐propranolol in rats using mechanism‐based estimations of in vivo receptor affinity (KB,vivo)

Cited by 8 publications

References 26 publications

Stereoselective binding of chiral drugs to plasma proteins

Stereoselective binding of chiral drugs to plasma proteins

The mastermind approach to CNS drug therapy: translational prediction of human brain distribution, target site kinetics, and therapeutic effects

PK/PD Modeling of β-Blockers in Cardiovascular Disease: An Update

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