Commentary  |
Inhaled Drug Delivery

How Are Inhaled Drugs Absorbed and Distributed in the Lungs?

30 June 2022
Inhaled drugs are a viable means of targeting tobacco smoke-related diseases in the lungs: permeability is key to their successful delivery. This Commentary article explores the mechanisms by which drugs are delivered across cell membranes, as well as pertinent areas for present and future research.

Presented by Carsten Ehrhardt, Professor in Pharmaceutics and Biopharmaceutics at Trinity College Dublin

Edited by Ben Norris

As a druggable target for inhalation therapies, the lung presents a unique challenge for those working in pharmaceutics. Different tissue and cell populations of the lung have distinct transporter expression patterns; to complicate things further, particles have to dissolve before they are removed by mucociliary clearance or phagocytosis. However, for Carsten Ehrhardt, Professor in Pharmaceutics at Trinity College Dublin the focus is on drug absorption into the lung tissue. As he explained to the audience at our Formulation and Delivery UK: In-Person event in May 2022, membrane transporters may also be novel drug targets in tobacco smoke-related diseases.


Action and Uptake of Inhaled Biologics

Carsten Ehrhardt kicked off his presentation by explaining that the focus of his research was not so much on getting material inside the lung. “We’re more interested in what happens when the particle or droplet is deposited,” Ehrhardt said. “Depending where you are in the central lung, the particle is probably sitting on the mucous layer, and needs to dissolve first before it’s removed by mucociliary clearance.” From here, the drug penetrates across the epithelial layer and into the lung tissue and bloodstream.

Inhaled drugs can then either stay in the epithelial cell or diffuse out into the tissue or the bloodstream. “As long as there’s a concentration gradient, this is a passive process that can go in both directions,” said Ehrhardt. “However, due to the pKa of the molecule many of these drugs have a net positive charge,” Ehrhardt continued. When interacting with a positively charged cell membrane, this creates trouble. In addition, charged hydrophilic molecules don’t like crossing the lipid bilayer. “So, while there’s a small percentage of molecules that might be net neutral and permeate across, it’s probably not the main absorption mechanism.”

So, how do molecules permeate across these membranes? Some molecules move across via passive diffusion, but this is not a main contributor to absorption. More significantly, molecules may be substrates for transporters protein localised in the cell membrane. “We have transporters in many biological barriers that help molecules across, and in some cases, they also recognise therapeutic molecules.” Ehrhardt gave the example of carbohydrates: sugars are hydrophilic molecules which are superficially unable to cross the cell membrane but are nonetheless are absorbed after a meal.

Transport of Inhaled Biologics: Membrane Transporters

One issue with drug uptake in the body is that different drugs may target the same transporter. “Currently, about half of newly FDA-approved molecular entities have patient information warnings about drug-drug interactions caused by transporters,” said Ehrhardt. In these interactions, two drugs will compete for the same transporter, which may impact on their pharmacokinetics, which are governed by drug absorption, distribution, metabolism and excretion.

As Ehrhardt explained, many researchers have not yet focused on transporters in the lungs, making them a relatively novel target in pulmonary drug development. He told the audience that his research had investigated ATP-binding cassette (ABC) transporters. “They have a binding site for ATP, so they can transport a substrate against the concentration gradient,” he said. These transporters efflux molecules out of the cell, which is a deleterious process in the gut as substrates are ‘kicked back out into the lumen.

“If you have this transporter sitting in the luminal side of the cell, it will recycle the drug back into the lung – that could be a potentially interesting mechanism to achieve a higher lung-residence time.”

However, in the lung the story is different. “If you have this transporter sitting in the luminal side of the cell, it will recycle the drug back into the lung,” said Ehrhardt. “That could be a potentially interesting mechanism to achieve a higher lung residence time.” The first transporter investigated for this was P-glycoprotein (P-gp/MDR1), which Ehrhardt introduced as “the best-known efflux transporter we have”.

Drug Transporter Studies

There are particular trends in inhaled drug permeability that can be monitored for, as Ehrhardt explained. “When you do a transport study – which means you grow your cells to a confluent layer on a permeable insert, you measure the bi-directional flux of the drug – if you have a passively-diffusing drug the permeability coefficients in absorptive and secretive directions should be the same.” In scenarios such as these where absorption is much slower than secretion, there is an indication that a luminal efflux transporter is present. In this instance, the transporter acts to hinder absorption.

Inhaled drugs and therapeutics. Assessment of ABCC1 / MRP1 activity in the lungs of rats.
Figure 1. Assessment of ABCC1 / MRP1 activity in the lungs of rats.

Ehrhardt then moved on to discussing the results from a mouse model, which investigated the adsorption of P-gp substrates from isolated perfused mouse lungs. In wildtype animals P-gp substrate drugs exhibit higher dwell times. “When you inhibit the transporter genetically or pharmacologically you have a quicker absorption and clearance, which clearly shows that the transporter is involved in pharmacokinetics.”

The other transporter Ehrhardt discussed was MRP1, which is a physiologically-relevant transporter because it excretes many endogenous substrates in addition to phase 2 metabolites from the cell. MRP1 is abundantly expressed at the lung epithelial barrier, where it may influence the pulmonary deposition of inhaled drugs and contribute to variability in the therapeutic response. Observations on lung kinetics in living rats found that the wild-type animals exhibited a much faster clearance of MRP1 substrates from the lung, and when the transporter is attenuated either by knockout or pharmacological inhibition, residence time in the lung is increased.

Future Implications for Inhalation Biopharmaceutical Research

Ehrhardt wrapped up his presentation by discussing the implications for the expression of efflux transporters in human lung epithelial cells. “A number of inhaled drugs have been found to interact with membrane transporters in vitro, ex vivo, and in vivo.” P-gp increases the pulmonary retention time of inhaled drugs, while MRP1 facilitates lung drug clearance, meaning inhaled drugs stay in the lung for longer. Transporters might be novel drug targets in chronic obstructive pulmonary disease (COPD) and other smoke-related diseases, because MRP1 expression is associated with COPD severity.

This is a pertinent area of research to focus on as similar studies may be applicable in humans to assess the effects of disease, genetic polymorphisms, or concomitant drug intake on pulmonary transporter activity. “I think we should consider these inter-individual variations, because we are not all the same and transporters are differently expressed and active in human beings,” Ehrhardt added. “And we see differences in pharmacokinetics based on that, as well as drug-drug interactions.”

Want to read more articles similar to this one? Head over to our Formulation portal for the latest news and research into delivery methods. If you want to know more about our upcoming Inhalation and Respiratory Drug Delivery Congresses in the UK and USA, visit our event websites for more information and details on how to register.

Speaker Biographies

Carsten is Professor in Pharmaceutics and Biopharmaceutics and Fellow at Trinity College Dublin. He also holds an Adjunct Professorship at the University of Southern California. His research is focused on lung drug disposition and pulmonary epithelial transport. Moreover; he is interested in molecular origins of airways disease. Carsten has edited 1 book and (co-) authored 102 peer-reviewed publications and over 250 abstracts. He is the recipient of honours and awards from German Pharmaceutical Society (DPhG); American Physiological Society and Galenus Foundation. Carsten serves as Associate Editor of Journal of Aerosol Medicine and Pulmonary Drug Delivery and Section Editor of European Journal of Pharmaceuticals Sciences.

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