iBCS: 3. A Biopharmaceutics Classification System for Orally Inhaled Drug Products.

In this article, we specify for the first time a quantitative biopharmaceutics classification system for orally inhaled drugs. To date, orally inhaled drug product developers have lacked a biopharmaceutics classification system like the one developed to navigate the development of immediate release of oral medicines. Guideposts for respiratory drug discovery chemists and inhalation product formulators have been elusive and difficult to identify due to the complexity of pulmonary physiology, the intricacies of drug deposition and disposition in the lungs, and the influence of the inhalation delivery device used to deliver the drug as a respirable aerosol. The development of an inhalation biopharmaceutics classification system (iBCS) was an initiative supported by the Product Quality Research Institute (PQRI). The goal of the PQRI iBCS working group was to generate a qualitative biopharmaceutics classification system that can be utilized by inhalation scientists as a "rule of thumb" to identify desirable molecular properties and recognize and manage CMC product development risks based on physicochemical properties of the drug and the deposited lung dose. Herein, we define the iBCS classes quantitatively according to the dose number and permeability. The proposed iBCS was evaluated for its ability to categorize marketed inhaled drugs using data from the literature. The appropriateness of the classification of each drug was assessed based on published development, clinical and nonclinical data, and mechanistic physiologically based biopharmaceutics modeling. The inhaled drug product development challenges for each iBCS classification are discussed and illustrated for different classes of marketed inhaled drugs. Finally, it is recognized that discriminatory laboratory methods to characterize regional lung deposition, dissolution, and permeability will be key to fully realizing the benefits of an iBCS to streamline and derisk inhaled drug development.

Orellanine: From Fungal Origin to a Potential Future Cancer Treatment.

Fungal metabolites represent an underutilized resource in the development of novel anticancer drugs. This review will focus on the promising fungal nephrotoxin orellanine, found in mushrooms including Cortinarius orellanus (Fools webcap). Emphasis will be placed on its historical significance, structural features, and associated toxicomechanics. Chromatographic methods for analysis of the compound and its metabolites, its synthesis, and chemotherapeutic potential are also discussed. Although orellanine's exceptional selectivity for proximal tubular cells is well documented, the mechanics of its toxicity in kidney tissue remains disputed. Here, the most commonly proposed hypotheses are detailed in the context of the molecule's structure, the symptoms seen following ingestion, and its characteristic prolonged latency period. Chromatographic analysis of orellanine and its related substances remains challenging, while biological evaluation of the compound is complicated by uncertainty regarding the role of active metabolites. This has limited efforts to structurally refine the molecule; despite numerous established methods for its synthesis, there is minimal published material on how orellanine's structure might be optimized for therapeutic use. Despite these obstacles, orellanine has generated promising data in preclinical studies of metastatic clear cell renal cell carcinoma, leading to the early 2022 announcement of phase I/II trials in humans.

Effect of budesonide on pulmonary activity of multidrug resistance-associated protein 1 assessed with PET imaging in rats.

Multidrug resistance-associated protein 1 (MRP1/ABCC1) is a highly abundant efflux transporter in the lungs, which protects cells from toxins and oxidative stress and has been implicated in the pathophysiology of chronic obstructive pulmonary disease and cystic fibrosis. There is evidence from in vitro studies that the inhaled glucocorticoid budesonide can inhibit MRP1 activity. We used positron emission tomography (PET) imaging with 6-bromo-7-[11C]methylpurine ([11C]BMP), which is transformed in vivo into a radiolabeled MRP1 substrate, to assess whether intratracheally (i.t.) aerosolized budesonide affects pulmonary MRP1 activity in rats. Three groups of rats (n = 5-6 each) underwent dynamic PET scans of the lungs after i.t. aerosolization of either [11C]BMP alone, or [11C]BMP mixed with either budesonide (0.04 mg, corresponding to the maximum soluble dose) or the model MRP1 inhibitor MK571 (2 mg). From PET-measured radioactivity concentration-time curves, the rate constant describing radioactivity elimination from the right lung (kE,lung) and the area under the curve (AUClung) were calculated from 0 to 5 min after start of the PET scan as measures of pulmonary MRP1 activity. Co-administration of MK571 resulted in a pronounced decrease in kE,lung (25-fold, p < 0.0001) and an increase in AUClung (5.3-fold, p < 0.0001) when compared with vehicle-treated animals. In contrast, in budesonide-treated animals kE,lung and AUClung were not significantly different from the vehicle group. Our results show that i.t. aerosolized budesonide at an approximately 5 times higher dose than the maximum clinical dose leads to no change in pulmonary MRP1 activity, suggesting a lack of an effect of inhaled budesonide treatment on the MRP1-mediated cellular detoxifying capacity of the lungs. However, the strong effect observed for MK571 raises the possibility for the occurrence of transporter-mediated drug-drug interactions at the pulmonary epithelium with inhaled medicines.

Influence of P-glycoprotein on pulmonary disposition of the model substrate [11C]metoclopramide assessed by PET imaging in rats.

In the lungs, the membrane transporter P-glycoprotein (P-gp) is expressed in the apical (i.e. lumen-facing) membrane of airway epithelial cells and in the luminal (blood-facing) membrane of pulmonary capillary endothelial cells. To better understand the influence of P-gp on the pulmonary disposition of inhaled P-gp substrate drugs, we measured the intrapulmonary pharmacokinetics of the intratracheally (i.t.) aerosolized model P-gp substrate [11C]metoclopramide in presence and absence of P-gp activity by means of positron emission tomography (PET) imaging in rats. Data were compared to data previously acquired with the model P-gp substrates (R)-[11C]verapamil and [11C]N-desmethyl-loperamide, using the same experimental set-up. Groups of wild-type rats, either untreated or treated with the P-gp inhibitor tariquidar, and Abcb1a/b(-/-) rats underwent 90-min dynamic PET scans after i.t. aerosolization of [11C]metoclopramide. Lung exposure to [11C]metoclopramide was expressed as the area under the right lung concentration-time curve (AUClung). AUClung values were significantly higher in Abcb1a/b(-/-) rats (1.8-fold, p ≤ 0.0001) and in tariquidar-treated wild-type rats (1.6-fold, p ≤ 0.01) than in untreated wild-type rats. This differed from previously obtained results with (R)-[11C]verapamil and [11C]N-desmethyl-loperamide, which showed decreased exposure in the rat lung in absence of P-gp activity. Our results suggest that transepithelial transfer of [11C]metoclopramide was not or only to a small extent affected by P-gp activity, presumably due to the compound's high passive permeability. The increased lung retention of [11C]metoclopramide may be due to decreased P-gp-mediated clearance into the blood in absence of P-gp activity in capillary endothelial cells. The overall effect of P-gp on the lung exposure to inhaled P-gp substrate drugs may, thus, be determined by a balance of opposing effects at the pulmonary epithelium and endothelium.

Knockout of ABCC1 in NCI-H441 cells reveals CF to be a suboptimal substrate to study MRP1 activity in organotypic in vitro models.

Multidrug resistance-associated protein 1 (MRP1/ABCC1) is an efflux transporter responsible for the extrusion of endogenous substances as well as xenobiotics and their respective metabolites. Its high expression levels in lung tissue imply a key role in pulmonary drug disposition. Moreover, its association with inflammatory lung diseases underline MRP1's relevance in drug development and precision-medicine. With the aim to develop a tool to better understand MRP1's role in drug disposition and lung disease, we generated an ABCC1-/- clone based on the human distal lung epithelial cell line NCI-H441 via a targeted CRISPR/Cas9 approach. Successful knockout (KO) of MRP1 was confirmed by qPCR, immunoblot and Sanger sequencing. To assess potential compensatory upregulation of transporters with a similar substrate recognition pattern as MRP1, expression levels of MRP2-9 as well as OAT1-4, 6, 7 and 10 were measured. Functional transporter activity was determined via release studies with two prodrug/substrate pairs, i.e. 5(6)-carboxyfluorescein (CF; formed from its diacetate prodrug) and S-(6-(7-methylpurinyl))glutathione (MPG; formed from its prodrug 6-bromo-7-methylpurine, BMP), respectively. Lastly, transepithelial electrical resistance (TEER) of monolayers of the KO clone were compared with wildtype (WT) NCI-H441 cells. Of eight initially generated clones, the M2 titled clone showed complete absence of mRNA and protein in accordance with the designed genome edit. In transport studies using the substrate CF, however, no differences between the KO clone and WT NCI-H441 cells were observed, whilst no differences in expression of potential compensatory transporters was noted. On the other hand, when using BMP/MPG, the release of MPG was reduced to 11.5% in the KO clone. Based on these results, CF appears to be a suboptimal probe for the study of MRP1 function, particularly in organotypic in vitro and ex vivo models. Our ABCC1-/- NCI-H441 clone further retained the ability to form electrically tight barriers, making it a useful model to study MRP1 function in vitro.

Nanotechnology as a tool to overcome macromolecules delivery issues.

Nanocarriers can deliver drugs to specific organs or cells, potentially bridging the gap between a drug's function and its interaction with biological systems such as human physiology. The untapped potential of nanotechnology stems from its ability to manipulate materials, allowing control over physical and chemical properties and overcoming drug-related problems, e.g., poor solubility or poor bioavailability. For example, most protein drugs are administered parenterally, each with challenges and peculiarities. Some problems faced by bioengineered macromolecule drugs leading to poor bioavailability are short biological half-life, large size and high molecular weight, low permeability through biological membranes, and structural instability. Nanotechnology emerges as a promising strategy to overcome these problems. Nevertheless, the delivery system should be carefully chosen considering loading efficiency, physicochemical properties, production conditions, toxicity, and regulations. Moving from the bench to the bedside is still one of the major bottlenecks in nanomedicine, and toxicological issues are the greatest challenges to overcome. This review provides an overview of biotech drug delivery approaches, associated nanotechnology novelty, toxicological issues, and regulations.

Nuclear medicine imaging methods as novel tools in the assessment of pulmonary drug disposition.

INTRODUCTION: Drugs for the treatment of respiratory diseases are commonly administered by oral inhalation. Yet surprisingly little is known about the pulmonary pharmacokinetics of inhaled molecules. Nuclear medicine imaging techniques (i.e. planar gamma scintigraphy, single-photon emission computed tomography [SPECT] and positron emission tomography [PET]) enable the noninvasive dynamic measurement of the lung concentrations of radiolabeled drugs or drug formulations. This review discusses the potential of nuclear medicine imaging techniques in inhalation biopharmaceutical research. AREAS COVERED: (i) Planar gamma scintigraphy studies with radiolabeled inhalation formulations to assess initial pulmonary drug deposition; (ii) imaging studies with radiolabeled drugs to assess their intrapulmonary pharmacokinetics; (iii) receptor occupancy studies to quantify the pharmacodynamic effect of inhaled drugs. EXPERT OPINION: Imaging techniques hold potential to bridge the knowledge gap between animal models and humans with respect to the pulmonary disposition of inhaled drugs. However, beyond the mere assessment of the initial lung deposition of inhaled formulations with planar gamma scintigraphy, imaging techniques have rarely been employed in pulmonary drug development. This may be related to several technical challenges encountered with such studies. Considering the wealth of information that can be obtained with imaging studies their use in inhalation biopharmaceutics should be further investigated.

Impact of P-gp and BCRP on pulmonary drug disposition assessed by PET imaging in rats.

P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) are two efflux transporters which are expressed in the apical (i.e. airway lumen-facing) membranes of lung epithelial cells. To assess the influence of P-gp and BCRP on the pulmonary disposition of inhaled drugs, we performed positron emission tomography (PET) imaging in rats after intratracheal aerosolization of two model P-gp/BCRP substrate radiotracers (i.e. [11C]erlotinib and [11C]tariquidar). We studied rat groups in which both transporters were active (i.e. wild-type rats), either of the two transporters was inactive (Abcb1a/b(-/-) and Abcg2(-/-) rats) or both transporters were inactive (Abcg2(-/-) rats in which pulmonary P-gp activity was inhibited by treatment with unlabeled tariquidar). PET-measured lung distribution data were compared with brain-to-plasma radioactivity concentration ratios measured in a gamma counter at the end of the PET scan. For [11C]erlotinib, lung exposure (AUClungs) was moderately but not significantly increased in Abcb1a/b(-/-) rats (1.6-fold) and Abcg2(-/-) rats (1.5-fold), and markedly (3.6-fold, p < 0.0001) increased in tariquidar-treated Abcg2(-/-) rats, compared to wild-type rats. Similarly, the brain uptake of [11C]erlotinib was substantially (4.5-fold, p < 0.0001) increased when both P-gp and BCRP activities were impaired. For [11C]tariquidar, differences in AUClungs between groups pointed into a similar direction as for [11C]erlotinib, but were less pronounced and lacked statistical significance. Our study demonstrates functional P-gp and BCRP activity in vivo in the lungs and further suggests functional redundancy between P-gp and BCRP in limiting the pulmonary uptake of a model P-gp/BCRP substrate, analogous to the blood-brain barrier. Our results suggest that pulmonary efflux transporters are important for the efficacy and safety of inhaled drugs and that their modulation may be exploited in order to improve the pharmacokinetic and pharmacodynamic performance of pulmonary delivered drugs.

Fyn-kinase and caveolin-1 in the alveolar epithelial junctional adherence complex contribute to the early stages of pulmonary fibrosis.

Current pathophysiological findings indicate that damage to the alveolar epithelium plays a decisive role in the development of idiopathic pulmonary fibrosis (IPF). The available pharmacological interventions (i.e., oral pirfenidone and nintedanib) only slow down progression of the disease, but do not offer a cure. In order to develop new drug candidates, the pathophysiology of IPF needs to be better understood on a molecular level. It has previously been reported that a loss of caveolin-1 (Cav-1) contributes to profibrotic processes by causing reduced alveolar barrier function and fibrosis-like alterations of the lung-parenchyma. Conversely, overexpression of caveolin-1 appears to counteract the development of fibrosis by inhibiting the inflammasome NLRP3 and the associated expression of interleukin-1ß. In this study, the interaction between Fyn-kinase and caveolin-1 in the alveolar epithelium of various bleomycin (BLM)/TGF-ß damage models using precision-cut lung slices (PCLS), wildtype (WT) and caveolin-1 knockout (KO) mice as well as the human NCI-H441 cell line, were investigated. In WT mouse lung tissues, strong signals for Fyn-kinase were detected in alveolar epithelial type I cells, whereas in caveolin-1 KO animals, expression shifted to alveolar epithelial type II cells. Caveolin-1 and Fyn-kinase were found to be co-localized in isolated lipid rafts of NCI-H441 cell membrane fractions. These findings were corroborated by co-immunoprecipitation studies in which a co-localization of Cav-1 and Fyn-kinase was detected in the cell membrane of the alveolar epithelium. After TGF-ß and BLM-induced damage to the alveolar epithelium both in PCLS and cell culture experiments, a decrease in caveolin-1 and Fyn-kinase was found. Furthermore, TEER (transepithelial electrical resistance) measurements indicated that TGF-ß and BLM have a damaging effect on cell-cell contacts and thus impair the barrier function in NCI-H441 cell monolayers. This effect was attenuated after co-incubation with the Fyn-kinase inhibitor, PP-2. Our data suggest an involvement of Fyn-kinase and caveolin-1 in TGF-ß/bleomycin-induced impairment of alveolar barrier function and thus a possible role in the early stages of pulmonary fibrosis. Fyn-kinase and/or its complex with caveolin-1 might, therefore, be novel therapeutic targets in IPF.

iBCS: 2. Mechanistic Modeling of Pulmonary Availability of Inhaled Drugs versus Critical Product Attributes.

This work is the second in a series of publications outlining the fundamental principles and proposed design of a biopharmaceutics classifications system for inhaled drugs and drug products (the iBCS). Here, a mechanistic computer-based model has been used to explore the sensitivity of the primary biopharmaceutics functional output parameters: (i) pulmonary fraction dose absorbed (Fabs) and (ii) drug half-life in lumen (t1/2) to biopharmaceutics-relevant input attributes including dose number (Do) and effective permeability (Peff). Results show the nonlinear sensitivity of primary functional outputs to variations in these attributes. Drugs with Do < 1 and Peff > 1 × 10-6 cm/s show rapid (t1/2 < 20 min) and complete (Fabs > 85%) absorption from lung lumen into lung tissue. At Do > 1, dissolution becomes a critical drug product attribute and Fabs becomes dependent on regional lung deposition. The input attributes used here, Do and Peff, thus enabled the classification of inhaled drugs into parameter spaces with distinctly different biopharmaceutic risks. The implications of these findings with respect to the design of an inhalation-based biopharmaceutics classification system (iBCS) and to the need for experimental methodologies to classify drugs need to be further explored.

iBCS: 1. Principles and Framework of an Inhalation-Based Biopharmaceutics Classification System.

For oral drugs, the formulator and discovery chemist have a tool available to them that can be used to navigate the risks associated with the selection and development of immediate release oral drugs and drug products. This tool is the biopharmaceutics classification system (giBCS). Unfortunately, no such classification system exists for inhaled drugs. The perspective outlined in this manuscript provides the foundational principles and framework for a classification system for inhaled drugs. The proposed classification system, an inhalation-based biopharmaceutics classification system (iBCS), is based on fundamental biopharmaceutics principles adapted to an inhalation route of administration framework. It is envisioned that a classification system for orally inhaled drugs will facilitate an understanding of the technical challenges associated with the development of new chemical entities and their associated new drug products (device and drug formulation combinations). Similar to the giBCS, the iBCS will be based on key attributes describing the drug substance (solubility and permeability) and the drug product (dose and dissolution). This manuscript provides the foundational aspects of an iBCS, including the proposed scientific principles and framework upon which such a system can be developed.

In vitro antioxidant and wound healing properties of baru nut extract (Dipteryx alata Vog.) in pulmonary epithelial cells for therapeutic application in chronic pulmonary obstructive disease (COPD).

Baru nuts (Dipteryx alata Vog.) are a native species from Brazil, rich in phenols and other antioxidants, with high socioeconomic value and possible pharmaceutical applications. Here we investigated baru nut ethanolic extract (BNEE) antioxidant and wound healing activities in human NCI-H441 and A549 lung epithelial cell lines for a possible use in conditions related to oxidative stress and wound healing impairments, such as chronic obstructive pulmonary disease (COPD). BNEE was characterised with high DPPH free radical scavenging activity and high total phenolics content, amongst them gallic acid, that was identified and quantified by HPLC. BNEE was not cytotoxic at concentrations studied, reduced the levels of reactive oxygen species before and during oxidative stress and increased wound healing in cell monolayers. These are the first steps to investigate the beneficial properties of baru in diseases related to oxidative stress and wound healing impairments such as COPD.

PET imaging to assess the impact of P-glycoprotein on pulmonary drug delivery in rats.

Several drugs approved for inhalation for the treatment of pulmonary diseases are substrates of the adenosine triphosphate-binding cassette (ABC) transporter P-glycoprotein (P-gp). P-gp is expressed in the apical membrane of pulmonary epithelial cells and could play a role in modulating the pulmonary absorption and distribution of inhaled drugs, thereby potentially contributing to variability in therapeutic response and/or systemic side effects. We developed a new in vivo experimental approach to assess the functional impact of P-gp on the pulmonary delivery of inhaled drugs in rats. By using positron emission tomography (PET) imaging, we measured the intrapulmonary pharmacokinetics of the model P-gp substrates (R)-[11C]verapamil ([11C]VPM) and [11C]-N-desmethyl-loperamide ([11C]dLOP) administered by intratracheal aerosolization in three rat groups: wild-type, Abcb1a/b(-/-) and wild-type treated with the P-gp inhibitor tariquidar. Lung exposure (AUClung_right) to [11C]VPM was 64% and 50% lower (p < 0.05) in tariquidar-treated and in Abcb1a/b(-/-) rats, respectively, compared to untreated wild-type rats. For [11C]dLOP, AUClung_right was 59% and 34% lower (p < 0.05) in tariquidar-treated and in Abcb1a/b(-/-) rats, respectively. Our results show that P-gp can affect the pulmonary disposition of inhaled P-gp substrates, whereby a decrease in P-gp activity may lead to lower lung exposure and potentially to a decrease in therapeutic efficacy. Our study highlights the potential of PET imaging with intratracheally aerosolized radiotracers to assess the impact of membrane transporters on pulmonary drug delivery, in rodents and potentially also in humans.

In vitro and ex vivo models in inhalation biopharmaceutical research - advances, challenges and future perspectives.

Oral inhalation results in pulmonary drug targeting and thereby reduces systemic side effects, making it the preferred means of drug delivery for the treatment of respiratory disorders such as asthma, chronic obstructive pulmonary disease or cystic fibrosis. In addition, the high alveolar surface area, relatively low enzymatic activity and rich blood supply of the distal airspaces offer a promising pathway to the systemic circulation. This is particularly advantageous when a rapid onset of pharmacological action is desired or when the drug is suffering from stability issues or poor biopharmaceutical performance following oral administration. Several cell and tissue-based in vitro and ex vivo models have been developed over the years, with the intention to realistically mimic pulmonary biological barriers. It is the aim of this review to critically discuss the available models regarding their advantages and limitations and to elaborate further which biopharmaceutical questions can and cannot be answered using the existing models.

COVID-19; current situation and recommended interventions.

BACKGROUND: The new coronavirus (SARS-COV-2) that emerged at the end of 2019 was stated in China and infected millions of people around the world, with the highest spread rate amongst humans compared with other coronaviruses. This paper aimed to review and analyse the published studies about COVID-19 diagnosis, prevention, and treatment. METHOD: The reviewed studies were clinical trials, in-vivo, in-vitro, guidelines, reports from the world health organization (WHO), and the centre for disease control and prevention (CDC) in addition to systemic reviews. All data extracted and analysed to stand on the latest updates and recommendations for fighting this severe attack of COVID-19. RESULTS: Most important antiviral therapy of COVID-19 clinical trials is still running without clear results, but a few trials have indicated the role of numerous drugs in the treatment of COVID-19. Specific recommendations for aerosol therapy should be followed for the management of COVID-19. CONCLUSION: Nature of COVID-19 is still not very clear, however, management of the condition is similar to the previous attacks of coronaviruses.

Organic Cation Transporters in the Lung-Current and Emerging (Patho)Physiological and Pharmacological Concepts.

Organic cation transporters (OCT) 1, 2 and 3 and novel organic cation transporters (OCTN) 1 and 2 of the solute carrier 22 (SLC22) family are involved in the cellular transport of endogenous compounds such as neurotransmitters, l-carnitine and ergothioneine. OCT/Ns have also been implicated in the transport of xenobiotics across various biological barriers, for example biguanides and histamine receptor antagonists. In addition, several drugs used in the treatment of respiratory disorders are cations at physiological pH and potential substrates of OCT/Ns. OCT/Ns may also be associated with the development of chronic lung diseases such as allergic asthma and chronic obstructive pulmonary disease (COPD) and, thus, are possible new drug targets. As part of the Special Issue "Physiology, Biochemistry and Pharmacology of Transporters for Organic Cations", this review provides an overview of recent findings on the (patho)physiological and pharmacological functions of organic cation transporters in the lung.

Tobacco Smoke and Inhaled Drugs Alter Expression and Activity of Multidrug Resistance-Associated Protein-1 (MRP1) in Human Distal Lung Epithelial Cells in vitro.

Multidrug resistance-associated protein-1 (MRP1/ABCC1) is highly expressed in human lung tissues. Recent studies suggest that it significantly affects the pulmonary disposition of its substrates, both after pulmonary and systemic administration. To better understand the molecular mechanisms involved, we studied the expression, subcellular localization and activity of MRP1 in freshly isolated human alveolar epithelial type 2 (AT2) and type 1-like (AT1-like) cells in primary culture, and in the NCI-H441 cell line. Moreover, the effect of cigarette smoke extract (CSE) and a series of inhaled drugs on MRP1 abundance and activity was investigated in vitro. MRP1 expression levels were measured by q-PCR and immunoblot in AT2 and AT1-like cells from different donors and in several passages of the NCI-H441 cell line. The subcellular localization of the transporter was studied by confocal laser scanning microscopy and cell surface protein biotinylation. MRP1 activity was assessed by bidirectional transport and efflux experiments using the MRP1 substrate, 5(6)-carboxyfluorescein [CF; formed intracellularly from 5(6)-carboxyfluorescein-diacetate (CFDA)] in AT1-like and NCI-H441 cell monolayers. Furthermore, the effect of CSE as well as several bronchodilators and inhaled corticosteroids on MRP1 abundance and CF efflux was investigated. MRP1 protein abundance increased upon differentiation from AT2 to AT1-like phenotype, however, ABCC1 gene levels remained unchanged. MRP1 abundance in NCI-H441 cells were comparable to those found in AT1-like cells. The transporter was detected primarily in basolateral membranes of both cell types which was consistent with net basolateral efflux of CF. Likewise, bidirectional transport studies showed net apical-to-basolateral transport of CF which was sensitive to the MRP1 inhibitor MK-571. Budesonide, beclomethasone dipropionate, salbutamol sulfate, and CSE decreased CF efflux in a concentration-dependent manner. Interestingly, CSE increased MRP1 abundance, whereas budesonide, beclomethasone dipropionate, salbutamol sulfate did not have such effect. CSE and inhaled drugs can reduce MRP1 activity in vitro, which implies the transporter being a potential drug target in the treatment of chronic obstructive pulmonary disease (COPD). Moreover, MRP1 expression level, localization and activity were comparable in human AT1-like and NCI-H441 cells. Therefore, the cell line can be a useful alternative in vitro model to study MRP1 in distal lung epithelium.

Advances in Pulmonary Drug Delivery.

Pulmonary drug delivery represents an attractive, non-invasive administration option. In addition to locally acting drugs, molecules that are intended to produce systemic effects can be delivered via the pulmonary route. Several factors need to be considered in the context of delivering drugs to or via the lungs-in addition to the drug itself, its formulation into an appropriate inhalable dosage form of sufficient stability is critical. It is also essential that this formulation is paired with a suitable inhaler device, which generates an aerosol of a particle/droplet size that ensures deposition in the desired region of the respiratory tract. Lastly, the patient's (patho-) physiology and inhalation manoeuvre are of importance. This Special Issue brings together recent advances in the areas of inhalation device testing, aerosol formulation development, use of in vitro and in silico models in pulmonary drug deposition and drug disposition studies, and pulmonary delivery of complex drugs, such as vaccines, antibiotics and peptides, to or via the lungs.