Lung Retention by Lysosomal Trapping of Inhaled Drugs Can Be Predicted  In Vitro  With Lung Slices

Bäckström, Erica; Boger, Elin; Lundqvist, Anders; Hammarlund‐Udenaes, Margareta; Fridén, Markus

doi:10.1016/j.xphs.2016.08.014

Cited by 26 publications

(20 citation statements)

References 24 publications

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“…These findings add substance to a range of conceptual models of salmeterol retention and pulmonary selectivity. These models include the recognition that salmeterol has a large unbound drug volume of distribution in the lungs ( V u,lung ) and retention driven by lysosomal trapping as determined with a lung slice methodology (Bäckström et al., 2016a , b ). Similarly, micro-kinetic models suggest that the retention of β-agonists is due to the interaction with the phospholipid membrane to produce a depot for maintenance of local efficacious drug concentrations around the target receptor (Sykes et al., 2014 ).…”

Section: Discussionmentioning

confidence: 99%

Uncovering the regional localization of inhaled salmeterol retention in the lung

et al. 2018

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Treatment of respiratory disease with a drug delivered via inhalation is generally held as being beneficial as it provides direct access to the lung target site with a minimum systemic exposure. There is however only limited information of the regional localization of drug retention following inhalation. The aim of this study was to investigate the regional and histological localization of salmeterol retention in the lungs after inhalation and to compare it to systemic administration. Lung distribution of salmeterol delivered to rats via nebulization or intravenous (IV) injection was analyzed with high-resolution mass spectrometry imaging (MSI). Salmeterol was widely distributed in the entire section at 5 min after inhalation, by 15 min it was preferentially retained in bronchial tissue. Via a novel dual-isotope study, where salmeterol was delivered via inhalation and d3-salmeterol via IV to the same rat, could the effective gain in drug concentration associated with inhaled delivery relative to IV, expressed as a site-specific lung targeting factor, was 5-, 31-, and 45-fold for the alveolar region, bronchial sub-epithelium and epithelium, respectively. We anticipate that this MSI-based framework for quantifying regional and histological lung targeting by inhalation will accelerate discovery and development of local and more precise treatments of respiratory disease.

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Section: Discussionmentioning

confidence: 99%

Uncovering the regional localization of inhaled salmeterol retention in the lung

et al. 2018

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“…So, colloids with high zeta potential (negative or positive) are electrically stabilized while colloids with low zeta potentials tend to coagulate or flocculate as outlined in the table. 16 (Figure 6 )…”

Section: Methodsmentioning

confidence: 99%

Inhaled Immunotherapy Administration for Lung Cancer; Efficient? Certainly Possible

et al. 2018

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Lung cancer is still diagnosed at a late stage in most lung cancer patients. Regarding Non-small Cell lung cancer there are novel therapies such as; tyrosine kinase inhibitors and immunotherapy. Currently we have two immunotherapies that can be used either as first-line treatment or second line treatment; pembrolizumab and nivolumab. A third one is being investigated as a combination of immunotherapy; ipilimumab. Aerosol treatment has been investigated for many diseases not only for the lung, but also for systematic diseases. The design of cups was found the most significant factor in producing significant effects. The comparison of cups reveals the design J as the most capable of reducing the droplets at a minimum size of mass median aerodynamic diameter (MMAD) MMAD=1.99. Drug effect comes second in sequence (F=62.04) showing that nivolumab is the most drastic preparation at low particle sizes (1.89), two drugs share an intermediate particle diameter (pembrolizumab and ipilimumab). In total drugs demonstrate a decreasing droplet size: Ipilimumab>Pembrolizumab> Nivolumab.

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“…Pulmonary tissue retention and distribution of absorbed/dissolved drug in the airways may be influenced by the physicochemical drug characteristics [ 57 , 58 ] of inhaled drugs or patient-specific characteristics of airways ( Figure 2 ). The tissue affinity, or pulmonary tissue partition coefficient, of an inhaled drug is likely the most important of these characteristics [ 25 ].…”

Section: Pulmonary Pharmacokinetic Processes Following Inhalation mentioning

confidence: 99%

“…The tissue affinity, or pulmonary tissue partition coefficient, of an inhaled drug is likely the most important of these characteristics [ 25 ]. For example, basic drug molecules are reported to be retained in the lung by lysosomal trapping [ 58 – 60 ]. The low permeability of inhaled drugs such as long-acting muscarinic receptor antagonists (LAMAs) or long-acting β 2 -agonists (LABAs) is also considered to result in long lung retention [ 58 , 60 – 62 ].…”

Section: Pulmonary Pharmacokinetic Processes Following Inhalation mentioning

confidence: 99%

“…For example, basic drug molecules are reported to be retained in the lung by lysosomal trapping [ 58 – 60 ]. The low permeability of inhaled drugs such as long-acting muscarinic receptor antagonists (LAMAs) or long-acting β 2 -agonists (LABAs) is also considered to result in long lung retention [ 58 , 60 – 62 ]. Further potential mechanisms that may increase pulmonary retention time include slow receptor off-kinetics [ 26 , 63 , 64 ], esterification in the lung tissue [ 65 ], and interaction with membrane lipid bilayers, the latter of which is proposed to account for the long duration of bronchodilation provided by the LABAs salmeterol and formoterol [ 66 ].…”

Section: Pulmonary Pharmacokinetic Processes Following Inhalation mentioning

confidence: 99%

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Inhaled Therapy in Respiratory Disease: The Complex Interplay of Pulmonary Kinetic Processes

Borghardt

Kloft

Sharma

2018

Canadian Respiratory Journal

203

189

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The inhalation route is frequently used to administer drugs for the management of respiratory diseases such as asthma or chronic obstructive pulmonary disease. Compared with other routes of administration, inhalation offers a number of advantages in the treatment of these diseases. For example, via inhalation, a drug is directly delivered to the target organ, conferring high pulmonary drug concentrations and low systemic drug concentrations. Therefore, drug inhalation is typically associated with high pulmonary efficacy and minimal systemic side effects. The lung, as a target, represents an organ with a complex structure and multiple pulmonary-specific pharmacokinetic processes, including (1) drug particle/droplet deposition; (2) pulmonary drug dissolution; (3) mucociliary and macrophage clearance; (4) absorption to lung tissue; (5) pulmonary tissue retention and tissue metabolism; and (6) absorptive drug clearance to the systemic perfusion. In this review, we describe these pharmacokinetic processes and explain how they may be influenced by drug-, formulation- and device-, and patient-related factors. Furthermore, we highlight the complex interplay between these processes and describe, using the examples of inhaled albuterol, fluticasone propionate, budesonide, and olodaterol, how various sequential or parallel pulmonary processes should be considered in order to comprehend the pulmonary fate of inhaled drugs.

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Lung Retention by Lysosomal Trapping of Inhaled Drugs Can Be Predicted In Vitro With Lung Slices

Cited by 26 publications

References 24 publications

Uncovering the regional localization of inhaled salmeterol retention in the lung

Uncovering the regional localization of inhaled salmeterol retention in the lung

Inhaled Immunotherapy Administration for Lung Cancer; Efficient? Certainly Possible

Inhaled Therapy in Respiratory Disease: The Complex Interplay of Pulmonary Kinetic Processes

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