Uncovering the regional localization of inhaled salmeterol retention in the lung

Abstract

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.

Revealing the Regional Localization and Differential Lung Retention of Inhaled Compounds by Mass Spectrometry Imaging

“…We have previously taken a step in this direction when we showed with MSI that inhaled salmeterol is selectively retained around its pharmacological target site in the bronchial subepithelium. (5) In this study we demonstrate that compounds of different chemical classes are retained in different patterns. By profiling chemically dissimilar inhaled drug molecules and the formulations thereof, we can start exploring how the spatial distribution of inhaled drug can be modulated and optimized to target diseased lung.…”

“…Jet nebulizer Swirler Ò (AMICI, Spring City, PA) was used, and the rats were dosed for 25 minutes to achieve targeted lung deposited doses (LDDs) of 600 lg/kg (salmeterol), 300 lg/kg (salbutamol), and 400 lg/kg (FP). The dose of salmeterol was chosen to match data from previous study, (5) the dose of salbutamol was chosen to match the salmeterol LDD in lmol/kg, and the dose of FP was chosen based on in-house physiologically based pharmacokinetic (PBPK) modeling (not published). The excipient DPPE-MPEG 2000 was used in the suspensions to stabilize the suspended particles from forming aggregates, that is, to formulate suspensions appropriate for nebulization, and will have marginal effect on the solubility of the compounds in the suspensions.…”

“…Rats were anesthetized at the time of sampling [time points, 2 and 30 minutes, were chosen based on a previously published study (5) ] with isoflurane (FORENE Ò ; Abbott Scandinavia AB, Solna, Sweden), and a terminal blood sample was collected as previously described (23) to isolate plasma and stored at -20°C until analysis. The heart and lungs were removed from the thorax en bloc.…”

“…(3,4) The lung is a highly heterogeneous organ and depending on the specific location of the respiratory disease process to be treated, the pharmacological target sites can be either centrally (tracheobronchial) or peripherally located. The regional localization of salmeterol distribution and retention at the pharmacological target site in the bronchial subepithelium (5) has already been described, but further studies are needed to address the knowledge gaps of how inhaled drugs of different chemical classes are spatially distributed across the lung substructures.…”

“…(22) Recently, we reported the use of MSI to evaluate the distribution and retention of salmeterol in lung tissue and the dependence of distribution on administration route (inhalation vs. IV). (5) In the same study, we introduced a new factor to assess targeting of compound in specific histological regions (epithelium, subepithelium, and alveolar bed) of the lung. The lung targeting factor describes the advantage with inhalation over systemic dosing at equivalent plasma concentrations.…”