Impact of Drug Administration Route on Drug Delivery and Distribution into the Lung: An Imaging Mass Spectrometry Approach

Abstract

During the last decade, significant technological improvements in mass spectrometry have had a great impact on drug discovery. The development of matrix-assisted laser desorption/ionization imaging mass spectrometry (MALDI-IMS) has set a new frontier for the study of the distribution of endogenous and exogenous molecules present within a tissue. MALDI-IMS is a surface sampling technique that allows not only the detection of multiple analytes but also gives the spatial distribution of those analytes. Active compounds for pulmonary disease need an optimal and well-studied delivery into the lungs, in order to assure distribution with greater penetration into the peripheral or the alveolar region of the lung to maximize the therapeutic effects. IMS is very useful in the field of drug discovery, showing drug delivery and distribution in the body and organs. In this study, we present a comparison between two different ways of carrying out pulmonary drug administration: inhalation of a nebulized aerosol of aqueous drug solutions and intratracheal administration, which is much simpler, not expensive and commonly used during in vivo screening. Tiotropium bromide is a long-acting anticholinergic medicine used for maintenance treatment of chronic obstructive pulmonary disease. In the present work, tiotropium was administered by nebulization and by intratracheal instillation to guinea pigs at doses able to induce significant anti-bronchoconstrictive activity. Lung samples were dissected, frozen, cryosectioned and coated with matrix (α-hydroxy-cinnamic acid). IMS analyses were performed using a MALDI-LTQ-Orbitrap XL. Using this technique we were able to compare different distributions of the drug depending on the method of administration.

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

“…The lung has been previously studied by MSI showing xenobiotic distribution in lung (19)(20)(21) or differences induced by inhalation and intratracheal administration. (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.…”

Btk Inhibitor RN983 Delivered by Dry Powder Nose-only Aerosol Inhalation Inhibits Bronchoconstriction and Pulmonary Inflammation in the Ovalbumin Allergic Mouse Model of Asthma

“…This technique requires hundreds of milligrams of micronized drug, but is the only technique that provides a uniform drug distribution throughout the lungs. (29)(30)(31)(32) Uniform lung distribution is possible as a high quality respirable aerosol is generated and maintained for a period long enough to allow the mice to inhale an efficacious deposited dose. (20) The deposited dose can be utilized to calculate a therapeutic index, (33) ensuring that the drug has an appropriate exposure multiple (usually >10) present to rule out the manifestation of any systemic side effects and is also useful when planning inhaled toxicology studies.…”

“…When the amount of drug is limited, direct administration methods are an option but all suffer from non-homogeneous deposition, with more drug concentrated along the central airways and less well represented in the parenchymal/alveolar regions. (29,30) Direct instillation methods including intranasal (34) or intratracheal liquid (31,32) and spray instillation (35) or dry-powder insufflation, (36,37) can be used as a screening tool to determine the approximate dose range for later inhalation studies, or to determine the ranking of efficacy/toxicity for a series of structurally similar drugs. (38) The current standard of care in asthma, inhaled b-agonist and steroid combination treatments, have a beneficial inhibition of the early asthmatic response (EAR) and the late asthmatic response (LAR), respectively.…”

Dry Powder and Nebulized Aerosol Inhalation of Pharmaceuticals Delivered to Mice Using a Nose-only Exposure System

“…This requires dose/response studies that achieve enough compound administered to the lungs to induce a measureable side effect. The only way currently to uniformly distribute large doses of drug into the lungs of multiple small animals simultaneously is nose-only inhalation 3 4 5 . The strengths and weaknesses of different inhalation exposure techniques have been recently reviewed 6 7 8 .…”

“…When the amount of drug is limited (mg quantities), direct administration methods are an option but all suffer from non-homogeneous deposition, with more drug concentrated along the central airways and less well represented in the parenchymal/alveolar regions 3 4 5 . The effective dose delivered by direct instillation is always higher and can never be directly compared to inhaled doses 4 .…”