Methacholine delays pulmonary absorption of inhaled β2-agonists due to competition for organic cation/carnitine transporters

Gnadt, Mirjam; Trammer, Beatrice; Freiwald, Matthias; Kardziev, Boris; Bayliss, Martin K.; Edwards, Chris D.; Schmidt, M; Friedel, Godehard; Högger, Petra

doi:10.1016/j.pupt.2011.12.009

Cited by 17 publications

(14 citation statements)

References 28 publications

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“…Alternatives to this approach include ex vivo lung slices that retain lung structural and organizational properties [148], and other perfusion models which allow for extracellular matrix and tissue factor involvement [149,150]. Three-dimensional (3D) organoid models have also been proposed for possible inclusion in biomedical research efforts [151][152][153].…”

Section: In Vitro Modelsmentioning

confidence: 99%

Animal Models Reflecting Chronic Obstructive Pulmonary Disease and Related Respiratory Disorders: Translating Pre-Clinical Data into Clinical Relevance

Tanner

Single

2019

J Innate Immun

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Chronic obstructive pulmonary disease (COPD) affects the lives of an ever-growing number of people worldwide. The lack of understanding surrounding the pathophysiology of the disease and its progression has led to COPD becoming the third leading cause of death worldwide. COPD is incurable, with current treatments only addressing associated symptoms and sometimes slowing its progression, thus highlighting the need to develop novel treatments. However, this has been limited by the lack of experimental standardization within the respiratory disease research area. A lack of coherent animal models that accurately represent all aspects of COPD clinical presentation makes the translation of promising in vitro data to human clinical trials exceptionally challenging. Here, we review current knowledge within the COPD research field, with a focus on current COPD animal models. Moreover, we include a set of advantages and disadvantages for the selection of pre-clinical models for the identification of novel COPD treatments.

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Section: In Vitro Modelsmentioning

confidence: 99%

Animal Models Reflecting Chronic Obstructive Pulmonary Disease and Related Respiratory Disorders: Translating Pre-Clinical Data into Clinical Relevance

Tanner

Single

2019

J Innate Immun

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“…47 However, the effect of methacholine on transport of b-agonists through competition for organic cation/carnitine transporters has been demonstrated in human lungs and linked to lung mechanics. 39 In other studies, active transport in isolated rat lungs has also been demonstrated for IgG transported by neonatal constant region fragment receptor 48 and the absorptive permeability transport of polyhydroxyethylaspartamide. 49 To fully exploit the potential of isolated perfused lungs to study the influence of drug transporters, it would be useful to establish best practice in performing such studies, for example, demonstration of saturation/concentrationdependency, use of inhibitors, controls, and genetic knockouts, confirmation of findings using complimentary techniques, and the demonstration that drug kinetics link to effect on lung mechanics.…”

Section: Isolated and Perfused Lung Modelsmentioning

confidence: 86%

“…Although rat lungs are the most commonly used, it is possible to use the lungs of genetic knockout mice 38 and lobes of human lungs. 39 Intrinsic and formulation-driven PK has been investigated following pulmonary administration of drugs to isolated perfused lungs. The rate and extent of drug transfer from airway to perfusate has been used to establish relationships with molecular properties, 22,40 permeability in epithelial cell models, 22,24 and drug absorption in vivo.…”

Section: Isolated and Perfused Lung Modelsmentioning

confidence: 99%

Current Progress Toward a Better Understanding of Drug Disposition Within the Lungs: Summary Proceedings of the First Workshop on Drug Transporters in the Lungs

Ehrhardt

Bäckman

Couet

et al. 2017

Journal of Pharmaceutical Sciences

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The School of Pharmacy and Pharmaceutical Sciences at Trinity College Dublin hosted the "1 Workshop on Drug Transporters in the Lungs" in September 2016 to discuss the impact of transporters on pulmonary drug disposition and their roles as drug targets in lung disease. The workshop brought together about 30 scientists from academia and pharmaceutical industry from Europe and Japan and addressed the primary questions: What do we know today, and what do we need to know tomorrow about transporters in the lung? The 3 themes of the workshop were: (1) techniques to study drug transporter expression and actions in the lungs; (2) drug transporter effects on pulmonary pharmacokinetics-case studies; and (3) transporters as drug targets in lung disease. Some of the conclusions of the workshop were: suitable experimental models that allow studies of transporter effects are available; data from these models convincingly show a contribution of both uptake and efflux transporters on pulmonary drug disposition; the effects of transporters on drug lung PK is now better conceptualized; some transporters are associated with lung diseases. However, more work is needed to establish which of the available models best translate to the clinical situation.

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“…The analysis of fenoterol and ipratropium was similar to the previously described method for  2 -agonists [11]. Briefly, 50µL of internal standard solution (salbutamol 1µg/mL in methanol) was added to a 1mL plasma sample.…”

Section: Analysis Of Fenoterol and Ipratropium Concentrations By Lc-mmentioning

confidence: 99%

Analysis of Fenoterol and Ipratropium Transfer from Human Lung Tissue into Human Plasma Using a Dynamic Dialysis Model

Trammer¹

2014

BJPR

Self Cite

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Aims:The aim of the current study was to establish a simple and yet as much as possible physiologic approach for a simulation of the pulmonary absorption process to compare different inhaled drugs or drug formulations. Methodology: We designed a dialysis setting that allowed monitoring the drug release from human lung tissue into a continuous-flow plasma compartment. For proof-of-concept experiments we chose the glucocorticoid fluticasone propionate (FP) as model compound. For subsequent experiments we selected a commercially available metered dose inhaler delivering a fixed combination of the short-acting ß 2 -agonist fenoterol and the muscarinic antagonist ipratropium bromide. Results: With the novel dynamic dialysis model we observed high drug transport rates from the lung tissue into plasma including an elimination phase. The concentration profile in the plasma compartment of our model system was similar to the plasma concentration courses after inhalation of FP. Compared to FP significantly higher drug fractions of Original Research ArticleBritish Journal of Pharmaceutical Research, 4(11): 1287Research, 4(11): -1299Research, 4(11): , 2014 1288 fenoterol and ipratropium bromide were released into plasma and the transfer of ipratropium was more pronounced compared to fenoterol. Again, concentration profiles in plasma were alike to those described in clinical studies. Conclusion:We suggest that this model is appropriate for rapid assessment of comparative diffusion behaviour of drugs or drug formulations from lung tissue into plasma.

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Methacholine delays pulmonary absorption of inhaled β2-agonists due to competition for organic cation/carnitine transporters

Cited by 17 publications

References 28 publications

Animal Models Reflecting Chronic Obstructive Pulmonary Disease and Related Respiratory Disorders: Translating Pre-Clinical Data into Clinical Relevance

Animal Models Reflecting Chronic Obstructive Pulmonary Disease and Related Respiratory Disorders: Translating Pre-Clinical Data into Clinical Relevance

Current Progress Toward a Better Understanding of Drug Disposition Within the Lungs: Summary Proceedings of the First Workshop on Drug Transporters in the Lungs

Analysis of Fenoterol and Ipratropium Transfer from Human Lung Tissue into Human Plasma Using a Dynamic Dialysis Model

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