The reassertion profiles of long acting β2-adrenoceptor agonists in the guinea pig isolated trachea and human recombinant β2-adrenoceptor

Patel, Sheena; Summerhill, Susan; Stanley, Maria; Perros-Huguet, Christelle; Trevethick, Michael A.

doi:10.1016/j.pupt.2010.11.004

Cited by 12 publications

(8 citation statements)

References 31 publications

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“…5C; Table 4). These data are in good agreement with historical data reported in the literature for salmeterol, formoterol, and indacaterol (Patel et al, 2011).…”

Section: Radioligand Binding Studiessupporting

confidence: 91%

“…Methodology to determine the persistence (duration of effect) and reassertion behavior (blockade of agonist receptor activation with an antagonist followed by the restoration of an agonist effect postwashout of all agents with no subsequent agonist addition) of b 2 -AR agonists were adapted from procedures previously described (Summerhill et al, 2008;Patel et al, 2011). In brief, 55,000 cells/well of b 2 -AR CHO cells were added to clear, V-bottomed, 96-well plates and then treated with one of the conditions detailed below.…”

Section: Lance Camp Assaysmentioning

confidence: 99%

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In Vitro Pharmacological Characterization of Vilanterol, a Novel Long-Actingβ₂-Adrenoceptor Agonist with 24-Hour Duration of Action

Slack

Barrett

Morrison

et al. 2012

J Pharmacol Exp Ther

106

124

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Vilanterol trifenatate (vilanterol) is a novel, long-acting b 2 -adrenoceptor (b 2 -AR) agonist with 24 h activity. In this study, we describe the preclinical pharmacological profile of vilanterol using radioligand binding and cAMP studies in recombinant assays as well as human and guinea pig tissue systems to characterize b 2 -AR binding and functional properties. Vilanterol displayed a subnanomolar affinity for the b 2 -AR that was comparable with that of salmeterol but higher than olodaterol, formoterol, and indacaterol. In cAMP functional activity studies, vilanterol demonstrated similar selectivity as salmeterol for b 2 -over b 1 -AR and b 3 -AR, but a significantly improved selectivity profile than formoterol and indacaterol. Vilanterol also showed a level of intrinsic efficacy that was comparable to indacaterol but significantly greater than that of salmeterol. In cellular cAMP production and tissue-based studies measuring persistence and reassertion, vilanterol had a persistence of action comparable with indacaterol and longer than formoterol. In addition, vilanterol demonstrated reassertion activity in both cell and tissue systems that was comparable with salmeterol and indacaterol but longer than formoterol. In human airways, vilanterol was shown to have a faster onset and longer duration of action than salmeterol, exhibiting a significant level of bronchodilation 22 h after treatment. From these investigations, the data for vilanterol are consistent, showing that it is a novel, potent, and selective b 2 -AR receptor agonist with a long duration of action. This pharmacological profile combined with clinical data is consistent with once a day dosing of vilanterol in the treatment of both asthma and chronic obstructive pulmonary disease (COPD).

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“…5C; Table 4). These data are in good agreement with historical data reported in the literature for salmeterol, formoterol, and indacaterol (Patel et al, 2011).…”

Section: Radioligand Binding Studiessupporting

confidence: 91%

Section: Lance Camp Assaysmentioning

confidence: 99%

In Vitro Pharmacological Characterization of Vilanterol, a Novel Long-Actingβ₂-Adrenoceptor Agonist with 24-Hour Duration of Action

Slack

Barrett

Morrison

et al. 2012

J Pharmacol Exp Ther

106

124

View full text Add to dashboard Cite

show abstract

“…This penchant is clearly illustrated in some previous publications investigating the mechanism of action of salmeterol [27,89]. However, the statement by Box and Draper [90] that 'all models are wrong but some are useful' should remind us that all models are merely coarse/incomplete descriptions, and, in this respect, novel data obtained using bronchodilators such as indacaterol have prompted a less resolute stance [18,91,92]. Thus, it isconceivable that all three mechanisms play significant roles ( Figure 5) and that it is only the prevalence of each mechanism that varies among the bronchodilators.…”

Section: Discussionmentioning

confidence: 98%

Cell membranes… and how long drugs may exert beneficial pharmacological activity in vivo

Vauquelin

2016

Brit J Clinical Pharma

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The time course of the beneficial pharmacological effect of a drug has long been considered to depend merely on the temporal fluctuation of its free concentration. Only in the last decade has it become widely accepted that target-binding kinetics can also affect in vivo pharmacological activity. Although current reviews still essentially focus on genuine dissociation rates, evidence is accumulating that additional micro-pharmacokinetic (PK) and -pharmacodynamic (PD) mechanisms, in which the cell membrane plays a central role, may also increase the residence time of a drug on its target. The present review provides a compilation of otherwise widely dispersed information on this topic. The cell membrane can intervene in drug binding via the following three major mechanisms: (i) by acting as a sink/repository for the drug; (ii) by modulating the conformation of the drug and even by participating in the binding process; and (iii) by facilitating the approach (and rebinding) of the drug to the target. To highlight these mechanisms, we focus on drugs that are currently used in clinical therapy, such as the antihypertensive angiotensin II type 1 receptor antagonist candesartan, the atypical antipsychotic agent clozapine and the bronchodilator salmeterol. Although the role of cell membranes in PK-PD modelling is gaining increasing interest, many issues remain unresolved. It is likely that novel biophysical and computational approaches will provide improved insights in the near future. IntroductionThe pharmacokinetic (PK) and pharmacodynamic (PD) properties of a drug are determinants of its efficacy and the duration of its clinical action [1]. PK and PD have long been considered to be separate disciplines, and the time course of the pharmacological effect of a drug has essentially been considered in terms of the temporal fluctuation of its free concentration [2]. In accordance with this principle, the frequently observed time lag between the concentration of a drug in the systemic circulation and its effect was initially attributed to slow equilibration between the plasma and a hypothetical target-surrounding 'effect compartment' [3]. By contrast, preclinical screening studies traditionally aim to optimize drug candidates in terms of only their efficacy and potency (i.e. PD properties). Inherent to this practice is the proposal that drug-target interactions are adequately described by equilibrium equations and, hence, that association and dissociation rates play only subordinate roles. In addition to a few noteworthy exceptions [4,5], it is only in the last decade that it has become fashionable to include binding kinetics as an additional criterion for clinical efficacy. This insight was largely sparked by the seminal articles by Swinney [6] and Copeland et al. [7]. The numerous review articles that have been published subsequently have focused mainly on long residence times. This property is now recognized to play a key role with respect to the clinical British Journal of Clinical Pharmacology Br J Clin Pharmacol (2016...

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“…While octanol/buffer solvent systems constitute the traditional surrogate and provides practical information in domain of physiological PKs, it may be justified to replace this organic component by biological membranes and artificial phospholipid bilayer systems when the purpose is to better comprehend complex binding mechanisms where the membrane is thought to play an important role at the vicinity of the receptors [54]. Indeed, while the former only provide information about the lipophilicity of the ligand, the latter also take account of the potential contribution of the lipid's polar headgroups and even the presence of cholesterol [55][56][57].…”

Section: Membranes Act As a Repositorymentioning

confidence: 99%

On the ‘micro’-pharmacodynamic and pharmacokinetic mechanisms that contribute to long-lasting drug action

Vauquelin

2015

Expert Opinion on Drug Discovery

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The PK profile, as well as the target dissociation kinetics of a drug, may fail to account for its long-lasting efficiency in intact tissues and in vivo. This lacuna could potentially be alleviated by incorporating some of the enumerated 'microscopic' mechanisms and, to unveil them, dedicated experiments on sufficiently physiologically relevant biological material like cell monolayers can already be implemented early on in the lead optimization process.

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The reassertion profiles of long acting β2-adrenoceptor agonists in the guinea pig isolated trachea and human recombinant β2-adrenoceptor

Cited by 12 publications

References 31 publications

In Vitro Pharmacological Characterization of Vilanterol, a Novel Long-Actingβ₂-Adrenoceptor Agonist with 24-Hour Duration of Action

In Vitro Pharmacological Characterization of Vilanterol, a Novel Long-Actingβ₂-Adrenoceptor Agonist with 24-Hour Duration of Action

Cell membranes… and how long drugs may exert beneficial pharmacological activity in vivo

On the ‘micro’-pharmacodynamic and pharmacokinetic mechanisms that contribute to long-lasting drug action

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The reassertion profiles of long acting β2-adrenoceptor agonists in the guinea pig isolated trachea and human recombinant β2-adrenoceptor

Cited by 12 publications

References 31 publications

In Vitro Pharmacological Characterization of Vilanterol, a Novel Long-Actingβ2-Adrenoceptor Agonist with 24-Hour Duration of Action

In Vitro Pharmacological Characterization of Vilanterol, a Novel Long-Actingβ2-Adrenoceptor Agonist with 24-Hour Duration of Action

Cell membranes… and how long drugs may exert beneficial pharmacological activity in vivo

On the ‘micro’-pharmacodynamic and pharmacokinetic mechanisms that contribute to long-lasting drug action

Contact Info

Product

Resources

About

In Vitro Pharmacological Characterization of Vilanterol, a Novel Long-Actingβ₂-Adrenoceptor Agonist with 24-Hour Duration of Action

In Vitro Pharmacological Characterization of Vilanterol, a Novel Long-Actingβ₂-Adrenoceptor Agonist with 24-Hour Duration of Action